Protein dyshomeostasis is identified as the hallmark of many age-related NDDs including Parkinson's disease (PD). PD is a progressive neurodegenerative disorder (NDD) characterized by the accumulation of misfolded proteins, particularly α-synuclein (α-syn) leading to formation of Lewy bodies and cause degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Disruption of the cell's normal protein balance, which occurs when cells experience stress, plays a key role in causing the formation of harmful protein clumps. Functional proteostasis relies on coordinated mechanisms involving posttranslational modifications (PTMs), molecular chaperones, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks maintain proper synthesis, folding, confirmation and degradation of protein such as α-syn protein in PD. These approaches include enhancing lysosomal function, promoting autophagy and modulating the unfolded protein response. Understanding the complex interactions between these pathways is essential for developing effective treatments. This review synthesizes current knowledge of various genes and molecular mechanisms underlying proteostasis disruption in PD and evaluates emerging therapeutic strategies that target multiple genes and pathways simultaneously. The finding highlights the potential of integrated approaches to restore protein homeostasis and prevent neurodegeneration, offering new directions for PD treatment development.

Protein aggregation and accumulation are hallmark features of neurodegenerative diseases. In Parkinson's disease, the progressive formation and propagation of α-synuclein aggregates-found in Lewy bodies and Lewy neurites-are closely linked to widespread neuronal dysfunction, dopaminergic neuron loss, and the emergence of both motor and nonmotor symptoms, including anosmia, cognitive decline, and depression. Despite their pathological significance, the mechanisms underlying the formation, spread, and clearance of these aggregates remain incompletely understood. In this review, we examine the cellular and molecular pathways responsible for the elimination of protein aggregates in the diseased brain. We first summarize various experimental models of α-synuclein pathology, followed by a discussion of the degradation mechanisms in neurons and glial cells under pathological conditions. These findings offer new insights into cell type-specific clearance pathways and highlight potential therapeutic targets for mitigating α-synuclein-associated toxicity in Parkinson's disease.

Autophagy is a catabolic process by which cells maintain cellular homeostasis through the degradation of dysfunctional cytoplasmic components, such as toxic misfolded proteins and damaged organelles, within the lysosome. It is a multistep process that is tightly regulated by nutrient, energy, and stress-sensing mechanisms. Autophagy plays a pivotal role in various biological processes, including protein and organelle quality control, defense against pathogen infections, cell metabolism, and immune surveillance. As a result, autophagy dysfunction is linked to a variety of pathological conditions. The role of autophagy in cancer is complex and dynamic. Depending on the context, autophagy can have both tumor-suppressive and pro-tumorigenic effects. In contrast, its role is more clearly defined in protein conformational disorders, where autophagy serves as a mechanism to reduce toxic protein aggregation, thereby improving cellular homeostasis. Because autophagy-based therapies hold promising potential for the treatment of cancer and protein conformational disorders, this review will highlight the latest findings and advancements in these areas.

Both genetic and environmental factors modulate the risk of Parkinson's disease. In this article, all these pathophysiologic processes that contribute to damages at the tissue, cellular, organelle, and molecular levels, and their effects are talked about.

Alzheimer's disease (AD) is currently the seventh leading cause of death worldwide. In this study, we explored the critical role of autophagy in AD pathology using a streptozotocin (STZ)-induced AD model in Wistar rats. The experimental groups included sham, STZ-induced AD, and STZ + MCC950-treated animals. Our findings revealed that administering two doses of STZ (3 mg/kg) intracerebroventricular at the interval of 48 h (on days 0 and 2), triggered autophagy, as evidenced by elevated levels of autophagy markers such as LC3II, ULK1, Beclin1, Ambra1, Cathepsin B, and a reduction in p62 levels. Behavioral assessments, including the water maze and novel object recognition tests, confirmed cognitive deficits and memory impairment, while the open-field test indicated increased anxiety in STZ-induced AD rats. In particular, treating the STZ-induced AD group with MCC950 (50 mg/kg) decreased the overexpression of autophagy-related proteins, which was consistent with better behavioral outcomes and lower anxiety. Overall, this study highlights new insights into AD pathophysiology and suggests potential therapeutic avenues.

Neurodegenerative diseases, contributing to the significant socioeconomic burden due to aging society, are gaining increasing interest. Despite each disease having different etiologies, neuroinflammation is believed to play a crucial role in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In addition to the pathogenic function of inflammation in the brain there is growing evidence that immune responses are essential for neuroregeneration. This review compares and contrasts the neuroinflammatory pathways that selected neurodegenerative diseases share and have in common. In AD, tau tangles and beta-amyloid plaques cause microglia and astrocytes to become activated in an inflammatory response. Alpha-synuclein aggregation stimulate neuroinflammation in Parkinson's disease, especially in the substantia nigra. In Multiple Sclerosis an autoimmune attack on myelin is connected to inflammation via invading immune cells. Commonalities include the release of pro-inflammatory mediators like cytokines and activation of signaling pathways such as NF-κB and MAPK. Comprehending these common routes is essential for discovering early diagnostic possibilities for the diseases and possible tailored treatments. Our work underscores the potential for insights into disease mechanisms. Identifying common targets offers promise for advancing our understanding and potential future treatment approaches across these debilitating disorders.

Autophagy-related (Atg) proteins catalyze autophagosome formation at the phagophore assembly site (PAS). The assembly of Atg proteins at the PAS follows a semihierarchical order, in which Atg8 is thought to be quite downstream but still able to control the size of autophagosomes. Yet, how Atg8 coordinates multiple branches of autophagy machinery to regulate autophagosomal size is not clear. Here, we show that, in yeast, Atg8 positively regulates the autophagy-specific phosphatidylinositol 3-OH kinase complex and the retrograde trafficking of Atg9 vesicles through interaction with Atg1. Mechanistically, Atg8 does not enhance the kinase activity of Atg1; instead, it recruits Atg1 to the surface of the phagophore likely to orient Atg1's activity toward select substrates, leading to efficient phagophore expansion. Artificial tethering of Atg1 kinase domains to Atg8s enhanced autophagy in yeast, human and plant cells and improved muscle performance in worms. We propose that Atg8-mediated relocation of Atg1 from the PAS scaffold to the phagophore is a critical step in positive autophagy regulation.

Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a hallmark of Parkinson's disease. In previous studies, we examined dopaminergic neuron-specific Atg7 autophagy-deficient mice and observed α-synuclein aggregation in vivo. Notably, p62 accumulation preceded synuclein deposition, resulting in the formation of inclusions containing both α-synuclein and p62. This pathological process led to dopamine neuron loss and age-related motor impairments, such as hindlimb defects in 120-week-old mice. In this study, we developed a mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to investigate these mechanisms further. The mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. Phosphorylated synuclein deposits were detected in the substantia nigra, hippocampus, and cortical regions reliant on dopaminergic pathways. Degeneration of dopaminergic neurons in the substantia nigra pars compacta was also observed, with neuron numbers declining with age. Interestingly, this mouse model displayed more severe motor deficits than Atg7 autophagy-deficient mice. This novel model offers a valuable platform for studying the interplay between α-synuclein expression, autophagy dysfunction, and neurodegeneration, as well as for testing therapeutic strategies targeting synucleinopathies. Our findings highlight the importance of aging in the manifestation of synuclein toxicity, mirroring the progression observed in patients with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.

Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through various mechanisms. One of the processes through which probiotics exert their beneficial effects on various cells and tissues is autophagy. Autophagy can assist in maintaining host homeostasis by stimulating the immune system and affecting numerous physiological and pathological responses. In this review, we particularly focus on autophagy impairments occurring in several human illnesses and investigate how probiotics affect the autophagy process under various circumstances.Abbreviation: AD: Alzheimer disease; AKT: AKT serine/threonine kinase; AMPK: 5'AMP-activated protein kinase; ATG: autophagy related; CCl4: carbon tetrachloride; CFS: cell-free supernatant; CMA: chaperone-mediated autophagy; CRC: colorectal cancer; EPS: L. plantarum H31 exopolysaccharide; HD: Huntington disease; HFD: high-fat diet; HPV: human papillomavirus; IFNG/IFN-γ: interferon gamma; IL6: interleukin 6; LGG: L. rhamnosus GG; LPS: lipopolysaccharide; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PD: Parkinson disease; Pg3G: pelargonidin-3-O-glucoside; PI3K: phosphoinositide 3-kinase; PolyQ: polyglutamine; ROS: reactive oxygen species; SCFAs: short-chain fatty acids; SLAB51: a novel formulation of lactic acid bacteria and bifidobacteria; Slp: surface layer protein (of acidophilus NCFM); SNCA: synuclein alpha; ULK1: unc-51 like autophagy-activating kinase 1; YB: B. longum subsp. infantis YB0411; YFP: yeast fermentate prebiotic.

Autophagy is the major degradation process in cells and is involved in a variety of physiological and pathological functions. While macroautophagy, which employs a series of molecular cascades to form ATG8-coated double membrane autophagosomes for degradation, remains the well-known type of canonical autophagy, microautophagy and chaperon-mediated autophagy have also been characterized. On the other hand, recent studies have focused on the functions of autophagy proteins beyond intracellular degradation, including noncanonical autophagy, also known as the conjugation of ATG8 to single membranes (CASM), and autophagy-related extracellular secretion. In particular, CASM is unique in that it does not require autophagy upstream mechanisms, while the ATG8 conjugation system is involved in a manner different from canonical autophagy. There have been many reports on the involvement of these autophagy-related mechanisms in neurodegenerative diseases, with Parkinson's disease (PD) receiving particular attention because of the important roles of several causative and risk genes, including LRRK2. In this review, we will summarize and discuss the contributions of canonical and noncanonical autophagy to cellular functions, with a special focus on the pathogenesis of PD.

α-Synuclein misfolds into pathological forms that lead to various neurodegenerative diseases known collectively as α-synucleinopathies. In this Review, we provide a comprehensive overview of pivotal advances in α-synuclein research. We examine structural features and physiological functions of α-synuclein and summarize current insights into key post-translational modifications, such as nitration, phosphorylation, ubiquitination, sumoylation and truncation, considering their contributions to neurodegeneration. We also highlight the existence of disease-specific α-synuclein strains and their mechanisms of pathological spread, and discuss seed amplification assays and PET tracers as emerging diagnostic tools for detecting pathological α-synuclein in clinical settings. We also discuss α-synuclein aggregation and clearance mechanisms, and review cell-autonomous and non-cell-autonomous processes that contribute to neuronal death, including the roles of adaptive and innate immunity in α-synuclein-driven neurodegeneration. Finally, we highlight promising therapeutic approaches that target pathological α-synuclein and provide insights into emerging areas of research.

Parkinson's disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such as α-synuclein in neurons. As one of the major intracellular degradation pathways, the autophagy-lysosome pathway plays an important role in eliminating these proteins. Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance of α-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson's disease. Moreover, multiple genes associated with the pathogenesis of Parkinson's disease are intimately linked to alterations in the autophagy-lysosome pathway. Thus, this pathway appears to be a promising therapeutic target for treatment of Parkinson's disease. In this review, we briefly introduce the machinery of autophagy. Then, we provide a description of the effects of Parkinson's disease-related genes on the autophagy-lysosome pathway. Finally, we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy-lysosome pathway and their applications in Parkinson's disease.

Parkinson's disease (PD) is a prevalent, chronic neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the substantia nigra and other brain regions. The aggregation of alpha-synuclein (α-syn) into Lewy bodies and neurites is a key pathological feature associated with PD and its progression. Many therapeutic studies aim to target these aggregated forms of α-syn to potentially slow down or stop disease progression in PD. This review provides a comprehensive analysis of recent clinical trials involving vaccines and monoclonal antibodies targeting α-syn. Specifically, UB-312, AFFITOPE PD01A, PD03A and ACI-7104.056 are designed to provoke an immune response against α-syn (active immunisation), while Prasinezumab and Cinpanemab, MEDI1341 and Lu AF82422 focus on directly targeting α-syn aggregates (passive immunisation). Despite some promising results, challenges such as variable efficacy and trial discontinuations persist. Future research must address these challenges to advance disease-modifying therapies for PD around this therapeutic target.

Protein aggregation occurs as a consequence of dysfunction in the normal cellular proteostasis, which leads to the accumulation of toxic fibrillar aggregates of certain proteins in the cell. Enhancing the activity of proteolytic pathways may serve as a way of clearing these aggregates in a cell, and consequently, autophagy has surfaced as a promising target for the treatment of neurodegenerative disorders. Several strategies involving small molecule compounds that stimulate autophagic pathway of cell have been discovered. However, despite many compounds having demonstrated favorable outcomes in experimental disease models, the translation of these findings into clinical benefits for patient's remains limited. Consequently, alternative strategies are actively being explored to effectively target neurodegeneration via autophagy modulation. Recently, newer approaches such as modulation of expression of autophagic genes have emerged as novel and interesting areas of research in this field, which hold promising potential in neuroprotection. Similarly, as discussed for the first time in this review, the use of autophagy-inducing nanoparticles by utilizing their physicochemical properties to stimulate the autophagic process, rather than relying on their role as drug carriers, offers a completely fresh avenue for targeting neurodegeneration without the risk of drug-associated adverse effects. This review provides fresh perspectives on developing autophagy-targeted therapies for neurodegenerative disorders. Additionally, it discusses the challenges and impediments of implementing these strategies to alleviate the pathogenesis of neurodegenerative disorders in clinical settings and highlights the prospects and directions of future research in this context.

Alzheimer's disease (AD) is a geriatric disorder that can be roughly classified into sporadic AD and hereditary AD. The latter is strongly associated with genetic factors, and its treatment poses greater challenges compared to sporadic AD. Rotating magnetic fields (RMF) is a non-invasive treatment known to have diverse biological effects, including the modulation of the central nervous system and aging. However, the impact of RMF on hereditary AD and its underlying mechanism remain unexplored. In this study, we exposed APP/PS1 mice to RMF (2 h/day, 0.2 T, 4 Hz) for a duration of 6 months. The results demonstrated that RMF treatment significantly ameliorated their cognitive and memory impairments, attenuated neuronal damage, and reduced amyloid deposition. Furthermore, RNA-sequencing analysis revealed a significant enrichment of autophagy-related genes and the PI3K/AKT-mTOR signaling pathway. Western blotting further confirmed that RMF activated autophagy and suppressed the phosphorylation of proteins associated with the PI3K/AKT/mTOR signaling pathway in APP/PS1 mice. These protective effects and the underlying mechanism were also observed in Aβ25-35-exposed HT22 cells. Collectively, our findings indicate that RMF improves cognitive and memory dysfunction in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway, thus highlighting the potential of RMF as a clinical treatment for hereditary AD.

Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl2) in the brain.

To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl2-induced Parkinson's disease (PD).

Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl2 (Gp II-Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo-treated plants.

ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ-amino butyric acid content and markedly improved the brain levels of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and decreased glycogen synthase kinase-3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa-light-chain-enhancer of activated B cells, Toll-like receptor 4, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 and caspase-1. Bcl-2-associated X-protein and B-cell leukemia/lymphoma 2 protein (Bcl-2) can significantly modify caspase-3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p-protein kinase-like ER kinase (PERK), glucose-regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin-1).

ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti-inflammatory, antioxidant, and anti-apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl-2 pathway.

Programmed cell death (PCD) is a form of cell death distinct from accidental cell death (ACD) and is also referred to as regulated cell death (RCD). Typically, PCD signaling events are precisely regulated by various biomolecules in both spatial and temporal contexts to promote neuronal development, establish neural architecture, and shape the central nervous system (CNS), although the role of PCD extends beyond the CNS. Abnormalities in PCD signaling cascades contribute to the irreversible loss of neuronal cells and function, leading to the onset and progression of neurodegenerative diseases. In this review, we summarize the molecular processes and features of different modalities of PCD, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and other novel forms of PCD, and their effects on the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), multiple sclerosis (MS), traumatic brain injury (TBI), and stroke. Additionally, we examine the key factors involved in these PCD signaling pathways and discuss the potential for their development as therapeutic targets and strategies. Therefore, therapeutic strategies targeting the inhibition or facilitation of PCD signaling pathways offer a promising approach for clinical applications in treating neurodegenerative diseases.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The development of PD is closely linked to genetic and environmental factors, with GBA1 variants being the most common genetic risk. Mutations in the GBA1 gene lead to reduced activity of the coded enzyme, glucocerebrosidase, which mediates the development of PD by affecting lipid metabolism (especially sphingolipids), lysosomal autophagy, endoplasmic reticulum, as well as mitochondrial and other cellular functions. Clinically, PD with GBA1 mutations (GBA1-PD) is characterized by particular features regarding the progression of symptom severity. On the therapeutic side, the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions. In this review, we explore the genotypic and phenotypic correlations, etiologic mechanisms, biomarkers, and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.

Cytopathology induced by methamphetamine (METH) is reminiscent of degenerative disorders such as Parkinson's disease, and it is characterized by membrane organelles arranged in tubulo-vesicular structures. These areas, appearing as clusters of vesicles, have never been defined concerning the presence of specific organelles. Therefore, the present study aimed to identify the relative and absolute area of specific membrane-bound organelles following a moderate dose (100 µM) of METH administered to catecholamine-containing PC12 cells. Organelles and antigens were detected by immunofluorescence, and they were further quantified by plain electron microscopy and in situ stoichiometry. This analysis indicated an increase in autophagosomes and damaged mitochondria along with a decrease in lysosomes and healthy mitochondria. Following METH, a severe dissipation of hallmark proteins from their own vesicles was measured. In fact, the amounts of LC3 and p62 were reduced within autophagy vacuoles compared with the whole cytosol. Similarly, LAMP1 and Cathepsin-D within lysosomes were reduced. These findings suggest a loss of compartmentalization and confirm a decrease in the competence of cell clearing organelles during catecholamine degeneration. Such cell entropy is consistent with a loss of energy stores, which routinely govern appropriate subcellular compartmentalization.

Parkinson's disease (PD), which is the second most common neurodegenerative disorder, is characterized by progressive movement impairment and loss of midbrain dopaminergic neurons in the substantia nigra. Although mutations in TMEM230 are linked to familial PD, the pathogenic mechanism underlying TMEM230-associated PD remains to be elucidated. To explore the effect of TMEM230 depletion in vivo, we created TMEM230 knockout rats using CRISPR-Cas9 technology. TMEM230 knockout rats did not exhibit any core features of PD, including impaired motor function, loss of dopaminergic neurons in the substantia nigra, or altered expression of proteins related to autophagy, the Rab family, or vesicular trafficking. In addition, no glial reactions were observed in TMEM230 knockout rats. These results indicate that depletion of TMEM230 may not lead to dopaminergic neuron degeneration in rats, further supporting that PD-associated TMEM230 mutations lead to dopaminergic neuron death by gain-of-toxic function.

Protein homeostasis or proteostasis is an equilibrium of biosynthetic production, folding and transport of proteins, and their timely and efficient degradation. Proteostasis is guaranteed by a network of protein quality control systems aimed at maintaining the proteome function and avoiding accumulation of potentially cytotoxic proteins. Terminal unfolded and dysfunctional proteins can be directly turned over by the ubiquitin-proteasome system (UPS) or first amassed into aggregates prior to degradation. Aggregates can also be disposed into lysosomes by a selective type of autophagy known as aggrephagy, which relies on a set of so-called selective autophagy receptors (SARs) and adaptor proteins. Failure in eliminating aggregates, also due to defects in aggrephagy, can have devastating effects as underscored by several neurodegenerative diseases or proteinopathies, which are characterized by the accumulation of aggregates mostly formed by a specific disease-associated, aggregate-prone protein depending on the clinical pathology. Despite its medical relevance, however, the process of aggrephagy is far from being understood. Here we review the findings that have helped in assigning a possible function to specific SARs and adaptor proteins in aggrephagy in the context of proteinopathies, and also highlight the interplay between aggrephagy and the pathogenesis of proteinopathies.

Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1β, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1β, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.

Impairment of autophagic-lysosomal pathways is increasingly being implicated in Parkinson's disease (PD). GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD) and are the commonest known genetic risk factor for PD. GBA1 mutations have been shown to cause autophagic-lysosomal impairment. Defective autophagic degradation of unwanted cellular constituents is associated with several pathologies, including loss of normal protein homeostasis, particularly of α-synuclein, and innate immune dysfunction. The latter is observed both peripherally and centrally in PD and GD. Here, we will discuss the mechanistic links between autophagy and immune dysregulation, and the possible role of these pathologies in communication between the gut and brain in these disorders. Recent work in a fly model of neuronopathic GD (nGD) revealed intestinal autophagic defects leading to gastrointestinal dysfunction and immune activation. Rapamycin treatment partially reversed the autophagic block and reduced immune activity, in association with increased survival and improved locomotor performance. Alterations in the gut microbiome are a critical driver of neuroinflammation, and studies have revealed that eradication of the microbiome in nGD fly and mouse models of PD ameliorate brain inflammation. Following these observations, lysosomal-autophagic pathways, innate immune signalling and microbiome dysbiosis are discussed as potential therapeutic targets in PD and GD. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study.

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the loss of dopaminergic neurons. Genetic factors, inflammatory responses, oxidative stress, metabolic disorders, cytotoxic factors, and mitochondrial dysfunction are all involved in neuronal death in neurodegenerative diseases. The risk of PD can be higher in aging individuals due to decreased mitochondrial function, energy metabolism, and AMP-activated protein kinase (AMPK) function. The potential of AMPK to regulate neurodegenerative disorders lies in its ability to enhance antioxidant capacity, reduce oxidative stress, improve mitochondrial function, decrease mitophagy and macroautophagy, and inhibit inflammation. In addition, it has been shown that modulating the catalytic activity of AMPK can protect the nervous system. This article reviews the mechanisms by which AMPK activation can modulate PD.

Globally cancer and Alzheimer's disease (AD) are two major diseases and still, there is no clearly defined molecular mechanism. There is an opposite relation between cancer and AD which are the proportion of emerging cancer was importantly slower in AD patients, whereas slow emerging AD in patients with cancer. In cancer, regulation of cell mechanisms is interrupted by an increase in cell survival and proliferation, while on the contrary, AD is related to augmented neuronal death, that may be either produced by or associated with amyloid-β (Aβ) and tau deposition. Stated that the probability that disruption of mechanisms takes part in the regulation of cell survival/death and might be implicated in both diseases. The mechanism of actions such as DNA-methylation, genetic polymorphisms, or another mechanism of actions that induce alteration in the action of drugs with significant roles in resolving the finding to repair and live or die might take part in the pathogenesis of these two ailments. The functions of miRNA, p53, Pin1, the Wnt signaling pathway, PI3 KINASE/Akt/mTOR signaling pathway GRK2 signaling pathway, and the pathophysiological role of oxidative stress are presented in this review as potential candidates which hypothetically describe inverse relations between cancer and AD. Innovative materials almost mutual mechanisms in the aetiology of cancer and AD advocates novel treatment approaches. Among these treatment strategies, the most promising use treatment such as tyrosine kinase inhibitor, nilotinib, protein kinase C, and bexarotene.

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.

Parkinson's disease is a yet incurable, age-related neurodegenerative disorder characterized by the aggregation of small neuronal protein α-synuclein into amyloid fibrils. Inhibition of this process is a prospective strategy for developing a disease-modifying treatment. We overview here small molecule, peptide, and protein inhibitors of α-synuclein fibrillization reported to date. Special attention was paid to the specificity of inhibitors and critical analysis of their action mechanisms. Namely, the importance of oxidation of polyphenols and cross-linking of α-synuclein into inhibitory dimers was highlighted. We also compared strategies of targeting monomeric, oligomeric, and fibrillar α-synuclein species, thoroughly discussed the strong and weak sides of different approaches to testing the inhibitors.

Autoimmune diseases (AD) account for a high percentage of the population. One of the most prevalent is autoimmune thyroiditis (AIT). However, the therapeutic effects of Buzhong Yiqi (BZYQ) decoction on AIT have not been studied yet. The majority of the present study was conducted on NOD.H-2h4 mice in an attempt to ascertain the therapeutic effects of BZYQ decoction on AIT.

The 0.05% sodium iodide water (NaI)-induced AIT mice model was established. A total of nine NOD.H-2h4 mice were randomly divided into three groups: the normal group provided with regular water, the model group drinking freely 0.05% NaI, and the treatment group treated with BZYQ decoction (9.56 g/kg) after NaI supplementation (NaI + BZYQ). BZYQ decoction was administered orally once daily for eight weeks. The thyroid histopathology test was used to measure the severity of lymphocytic infiltration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of anti-thyroglobulin antibody (TgAb), interleukin (IL)-1β, IL-6, and IL-17. The Illumina HiSeq X sequencing platform was utilized to analyze the thyroid tissue by mRNA expression profiles. Bioinformatics analysis was used to investigate the biological function of the differentially expressed mRNAs. In addition, the expression of Carbonyl Reductase 1 (CBR1), 6-Pyruvoyltetrahydropterin Synthase (PTS), Major Histocompatibility Complex, Class II (H2-EB1), Interleukin 23 Subunit Alpha (IL-23A), Interleukin 6 Receptor (IL-6RA), and Janus Kinase 1 (JAK1) was measured by quantitative real-time PCR (qRT-PCR).

The treatment group exhibited significantly lower rates of thyroiditis and lymphocyte infiltration compared to the model group. Serum levels of TgAb, IL-1β, IL-6, and IL-17 were significantly higher in the model group, but they fell dramatically after BZYQ decoction administration. According to our results, 495 genes showed differential expression in the model group compared to the control group. Six hundred twenty-five genes were significantly deregulated in the treatment group compared to the model group. Bioinformatic analysis showed that most mRNAs were associated with immune-inflammatory responses and were involved in multiple signaling pathways, including folate biosynthesis and the Th17 cell differentiation pathway. CBR1, PTS, H2-EB1, IL- 23A, IL-6RA and JAK1 mRNA participated in folate biosynthesis and the Th17 cell differentiation pathway. The qRT-PCR analysis confirmed that the above mRNAs were regulated in the model group compared to the treatment group Conclusion: The results of this investigation have revealed novel insights into the molecular mechanism of action of BZYQ decoction against AIT. The mechanism may be partially attributed to the regulation of mRNA expression and pathways.

The pervasiveness and mortality associated with methamphetamine abuse have doubled during the past decade, suggesting a possible worldwide substance use crisis. Epitomizing the pathophysiology and toxicology of methamphetamine abuse proclaims severe signs and symptoms of neurotoxic and neurobehavioral manifestations in both humans and animals. Most importantly, chronic use of this drug enhances the probability of developing neurodegenerative diseases manifolds. Parkinson's disease is one such neurological disorder, which significantly and evidently not only shares a number of toxic pathogenic mechanisms induced by methamphetamine exposure but is also interlinked both structurally and genetically. Methamphetamine-induced neurodegeneration involves altered dopamine homeostasis that promotes the aggregation of α-synuclein protofibrils in the dopaminergic neurons and drives these neurons to make them more vulnerable to degeneration, as recognized in Parkinson's disease. Moreover, the pathologic mechanisms such as mitochondrial dysfunction, oxidative stress, neuroinflammation and decreased neurogenesis detected in methamphetamine abusers dramatically resemble to what is observed in Parkinson's disease cases. Therefore, the present review comprehensively cumulates a holistic illustration of various genetic and molecular mechanisms putting across the notion of how methamphetamine administration and intoxication might lead to Parkinson's disease-like pathology and Parkinsonism.

It is known that inflammation plays a role in the etiopathogenesis of schizophrenia. In this study, we examined high mobility group box 1 protein (HMGB1) and Beclin 1 levels and their relationship with clinical variables in patients with schizophrenia.

Forty-three patients with schizophrenia and 43 healthy controls were included in this study. The patients were administered sociodemographic data form, the Positive Negative Symptoms Assessment Scale (PANSS) and the Clinical Global Impressions (CGI) scale. After the scales were filled, venous blood samples were taken from both the patient and control groups to measure serum HMGB1 and Beclin 1 levels. Serum samples obtained at the end of centrifugation were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA) method.

The mean serum HMGB1 levels were significantly increased and the mean serum Beclin 1 levels were significantly decreased in the schizophrenia group compared to the control group. In addition, a negative correlation was found between HMGB1 and Beclin 1 levels.

In conclusion, current research shows that HMGB1 is increased and Beclin 1 is decreased in patients with schizophrenia, and these findings may contribute to the role of autophagy in the pathogenesis of schizophrenia.

Parkinson's disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, specifically the motor system. It is mainly caused by the loss of dopamine due to the accumulation of α-synuclein (α-syn) protein in the striatum and substantia nigra pars compacta (SNpc). Previous studies have reported that immunization may be a potential preventive strategy for neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Therefore, the aim of the study was to design an α-syn specific epitope vaccine and investigate its effect in PD-related pathophysiology using an α-syn-induced mouse model. We used an in silico model to identify and design a non-toxic α-syn-based peptide epitope vaccine and, to overcome poor immunogenicity, the vaccine was coupled with immunogenic carrier proteins, i.e., ovalbumin (OVA) and keyhole limpet haemocyanin (KLH). Our results showed that vaccinated PD mouse models, especially with vaccines with carrier proteins, improved in motor functions compared with the non-vaccinated PD model. Additionally, the vaccinated groups showed increased immunoglobulin G (IgG) levels in the spleen and plasma as well as decreased interleukin-10 (IL-10) levels in the plasma. Furthermore, vaccinated groups, especially OVA and KLH groups, showed decrease in α-syn levels and increased dopamine-related markers, i.e., tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and dopamine transporter (DAT), and autophagy activities in the striatum and SNpc. Lastly, our data showed decreased neuroinflammation by reducing the activation of microglia and astrocytes and pro-inflammatory cytokines in the immunized groups, especially with OVA and KLH carrier proteins. Overall, these results suggest that vaccination, especially with immunogenic carrier proteins, is effective in reducing the accumulation of α-syn aggregates in the brain and ameliorate PD-related pathophysiology. Hence, further development of this approach might have a potential role in preventing the development of PD.

Parkinson's disease (PD) is a challenge because of the ageing of the population and the disease's complicated pathogenesis. Accumulating evidence showed that iron and autophagy were involved in PD. Nevertheless, the molecular mechanism and role of iron and autophagy in PD are not yet elucidated. In the present study, it was shown that PD mice had significant motor dysfunction, increased iron content, less dopamine neurons and more α-synuclein accumulation in the substantia nigra. Meanwhile, PD mice treated with deferoxamine exhibited less iron content, relieved the dyskinesia and had a significant increase in dopamine neurons and a significant decrease in α-synuclein. Autophagy induced by LC3 was inhibited in PD models with iron treatment. Following verification showed that iron aggregation restrained insulin-like growth factor 2 (IGF2) and transcription factor zinc finger protein 27 (ZFP27) in PD models. In addition, LC3-induced autophagy flux was reduced with ZFP27 knockdown. Furthermore, ZFP27 affected autophagy by regulating LC3 promoter activity. These data suggest that iron deposition inhibits IGF2 and ZFP27 to reduce LC3-induced autophagy, and ultimately decrease dopamine neurons, accelerating PD progression. Our findings provide a novel insight that ZFP27-mediated iron-related autophagy and IGF2 may activate the downstream kinase gene to trigger autophagy in the PD model.

Defective autophagy is one of the cellular hallmarks of Parkinson's disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of Acanthopanax senticosus. It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in C. elegans, degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome-lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting SIRT1. The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.

Since glucose reuptake by neurons is mostly independent of insulin, it has been an intriguing question whether insulin has or not any roles in the brain. Consequently, the identification of insulin receptors in the central nervous system has fueled investigations of insulin functions in the brain. It is also already known that insulin can influence glucose reuptake by neurons, mostly during activities that have the highest energy demand. The identification of high density of insulin receptors in the hippocampus also suggests that insulin may present important roles related to memory. In this context, studies have reported worse performance in cognitive tests among diabetic patients. In addition, alterations in the regulation of central insulin pathways have been observed in the brains of Alzheimer's disease (AD) patients. In fact, some authors have proposed AD as a third type of diabetes and recently, our group proposed insulin resistance as a common link between different AD hypotheses. Therefore, in the present narrative review, we intend to revise and gather the evidence of disturbed insulin signaling in experimental animal models of AD.

Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed light on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with mass spectrometry-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma and might be a key hub protein associated with inflammation, proliferation, and autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide-induced inflammation, and autophagy marker increase was accompanied by autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated autophagy and promoted cell proliferation and migration, especially under lipopolysaccharide inflammatory stimulation. Moreover, inhibiting autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/AKT/CyclinD1 pathways. Also, 740Y-P, a PI3K activator reversed the suppression of autophagy and PI3K signaling by siATG5 in SNCA-overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and autophagy may be a promising new target for treating cholesteatoma.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson's disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

Autophagy is a highly conserved biological process that has evolved across evolution. It can be activated by various external stimuli including oxidative stress, amino acid starvation, infection, and hypoxia. Autophagy is the primary mechanism for preserving cellular homeostasis and is implicated in the regulation of metabolism, cell differentiation, tolerance to starvation conditions, and resistance to aging. As a multifunctional protein, DJ-1 is commonly expressed in vivo and is associated with a variety of biological processes. Its most widely studied role is its function as an oxidative stress sensor that inhibits the production of excessive reactive oxygen species (ROS) in the mitochondria and subsequently the cellular damage caused by oxidative stress. In recent years, many studies have identified DJ-1 as another important factor regulating autophagy; it regulates autophagy in various ways, most commonly by regulating the oxidative stress response. In particular, DJ-1-regulated autophagy is involved in cancer progression and plays a key role in alleviating neurodegenerative diseases(NDS) and defective reperfusion diseases. It could serve as a potential target for the regulation of autophagy and participate in disease treatment as a meaningful modality. Therefore, exploring DJ-1-regulated autophagy could provide new avenues for future disease treatment.

Phagocytosis plays an important role in maintaining brain homeostasis and when impaired can result in the accumulation of unwanted cellular material. While microglia are traditionally considered the phagocytes of the brain, astrocytes are also capable of phagocytosis and are the most numerous cells in the brain. In Alzheimer's disease (AD), astrocytes can be found surrounding β-amyloid (Aβ) plaques yet they seem unable to eliminate these deposits, suggesting phagocytosis may be impaired in AD. Mechanisms that might diminish astrocyte phagocytosis in AD are currently unclear. Here, we demonstrate that the autophagy protein beclin 1, which is reduced in AD, plays a role in regulating astrocyte phagocytosis. Specifically, we show that reducing beclin 1 in C6 astrocytes impairs the phagocytosis of latex beads, reduces retromer levels, and impairs retromer recruitment to the phagosomal membrane. Furthermore, we show that these beclin 1-mediated changes are accompanied by reduced expression of the phagocytic receptor Scavenger Receptor Class B type I (SR-BI). Collectively, these findings suggest a critical role for the protein beclin 1 in both receptor trafficking and receptor-mediated phagocytosis in astrocytes. Moreover, these findings provide insight into mechanisms by which astrocytes may become impaired in AD.

(1) Background: Parkinson's disease (PD) is the most common movement disorder. Imbalanced protein homeostasis and α-syn aggregation are involved in PD pathogenesis. Autophagy is related to the occurrence and development of PD and can be regulated by histone deacetylases (HDACs). Various inhibitors of HDACs exert neuroprotective effects within in vitro and in vivo models of PD. HDAC4, a class Ⅱ HDAC, colocalizes with α-synuclein and ubiquitin in Lewy bodies and also accumulates in the nuclei of dopaminergic neurons in PD models. (2) Methods: In the present study, the gene expression profile of HDACs from two previously reported datasets in the GEO database was analyzed, and the RNA levels of HDAC4 in brain tissues were compared between PD patients and healthy controls. In vitro, SH-SY5Y cells transfected with HDAC4 shRNA or pretreated with mc1568 were treated with 1 μM of rotenone for 24 h. Then, the levels of α-syn, LC3, and p62 were detected using Western blot analysis and immunofluorescent staining, and cell viabilities were detected using Cell Counting Kit-8 (CCK-8). (3) Results: HDAC4 was highly expressed in PD substantia nigra and locus coeruleus. Mc1568, an inhibitor of HDAC4, decreased α-synuclein levels in rotenone-treated SH-SY5Y cells in a concentration-dependent manner and activated autophagy, which was impaired by rotenone. The knockdown of HDAC4 reversed rotenone-induced α-syn accumulation in SH-SY5Y cells and protected the neurons by enhancing autophagy. (4) Conclusions: HDAC4 is a potential therapeutic target for PD. The inhibition of HDAC4 by mc1568 or a gene block can reduce α-syn levels by regulating the autophagy process in PD. Mc1568 is a promising therapeutic agent for PD and other disorders related to α-syn accumulation.

Macroautophagy, herein referred to as autophagy, has long been implicated in the pathophysiology of neurodegenerative diseases. However, an incomplete understanding of how autophagy contributes to disease pathogenesis has limited progress in acting on this potential target for the development of disease modifying therapeutics. Research in the past few decades has revealed that autophagy plays a specialized role in the synapse, a site of early dysfunction in multiple neurodegenerative diseases. In this review we discuss the evidence suggesting that inadequate autophagy at the synapse may contribute to neurodegeneration, and why the functions of autophagy may be particularly relevant for synaptic function.

Aggrephagy describes the selective lysosomal transport and turnover of cytoplasmic protein aggregates by macro-autophagy. In this process, protein aggregates and conglomerates are polyubiquitinated and then sequestered by autophagosomes. Soluble selective autophagy receptors (SARs) are central to aggrephagy and physically bind to both ubiquitin and the autophagy machinery, thus linking the cargo to the forming autophagosomal membrane. Because the accumulation of protein aggregates is associated with cytotoxicity in several diseases, a better molecular understanding of aggrephagy might provide a conceptual framework to develop therapeutic strategies aimed at delaying the onset of these pathologies by preventing the buildup of potentially toxic aggregates. We review recent advances in our knowledge about the mechanism of aggrephagy.

The progressive aging of the population and the fact that Parkinson's disease currently does not have any curative treatment turn out to be essential issues in the following years, where research has to play a critical role in developing therapy. Understanding this neurodegenerative disorder keeps advancing, proving the discovery of new pathogenesis-related genes through genome-wide association analysis. Furthermore, the understanding of its close link with the disruption of autophagy mechanisms in the last few years permits the elaboration of new animal models mimicking, through multiple pathways, different aspects of autophagic dysregulation, with the presence of pathological hallmarks, in brain regions affected by Parkinson's disease. The synergic advances in these fields permit the elaboration of multiple therapeutic strategies for restoring autophagy activity. This review discusses the features of Parkinson's disease, the autophagy mechanisms and their involvement in pathogenesis, and the current methods to correct this cellular pathway, from the development of animal models to the potentially curative treatments in the preclinical and clinical phase studies, which are the hope for patients who do not currently have any curative treatment.