• Cerebellum
• Degeneration
• Granule cell
• Purkinje cell
• Regeneration
• Spinocerebellar ataxia
• Zebrafish

• Animals
• Zebrafish/genetics
• Cerebellum/metabolism
• Cerebellum/pathology
• Disease Models, Animal
• Humans
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/pathology
• Neurons/metabolism
• Nerve Regeneration/genetics
• Nerve Regeneration/physiology

• 427719460 Deutsche Forschungsgemeinschaft
• HOMEO-HIRN ZN3673 Volkswagen Foundation
• H2020-MSCA-IF-2015, grant agreement No 703961 Horizon 2020

• Hereditary Ataxia
• Hereditary Spinocerebellar Degenerations
• Machado-Joseph disease
• Spinocerebellar Diseases
• Trinucleotide Repeat Expansions

• Humans
• Male
• Peptides/genetics
• Female
• Spinocerebellar Ataxias/genetics
• Adult
• Middle Aged
• Phenotype
• Trinucleotide Repeat Expansion/genetics
• Age of Onset
• Prospective Studies
• Young Adult
• Aged
• Cohort Studies
• DNA Repeat Expansion/genetics

• Universidade do Porto

• free energy
• metastatistics
• protein stability
• protein variant
• unfolding

• Ataxia
• Cerebellum
• Dentate nucleus
• MRI
• Quantitative susceptibility mapping
• Spinocerebellar ataxia type 6

• Humans
• Adolescent
• Young Adult
• Adult
• Middle Aged
• Aged
• Spinocerebellar Ataxias/diagnostic imaging
• Spinocerebellar Ataxias/pathology
• Cerebellum/pathology
• Cerebellar Cortex/diagnostic imaging
• Cerebellar Cortex/pathology
• Cerebellar Nuclei/diagnostic imaging
• Magnetic Resonance Imaging/methods
• Atrophy/pathology

• Ataxia
• CB1R
• Cannabinoid
• Cerebellum
• Purkinje cell

• Ataxia
• Cannabinoid
• Cerebellum
• GABA
• TRP
• mGluR1

• Cerebellar ataxia
• Common signaling pathway
• Diagnosis
• Lipid homeostasis
• Treatment

• Ataxia/pathology
• Cerebellar Ataxia/diagnosis
• Cerebellar Ataxia/genetics
• Cerebellum/pathology
• Humans
• Lipids
• Spinocerebellar Degenerations/pathology

• cancer
• frataxin
• high-performance computing
• iron homeostasis
• molecular statistics

• Friedreich Ataxia/genetics
• Friedreich Ataxia/metabolism
• Humans
• Iron-Binding Proteins/genetics
• Iron-Binding Proteins/metabolism
• Protein Unfolding
• Thermodynamics
• Frataxin

• MIUR-PRIN-201744NR8S Governo Italiano

• 3-AP
• Cerebellar ataxia
• Cerebellum
• Neurodegenerative disease
• Olfactory stem cells
• Stereology

• Animals
• Humans
• Rats
• Cerebellar Ataxia/therapy
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Olfactory Mucosa

• interchangeability
• iron
• magnesium
• manganese
• metalloprotein
• metals
• reactive oxygen species
• redox regulation
• ribosome
• superoxide dismutase

• Enzymes/metabolism
• Evolution, Chemical
• Metals/metabolism
• Proteins/metabolism

• R01 GM114308 NIGMS NIH HHS

The severe acute respiratory syndrome coronavirus 2 has led to the worldwide pandemic named coronavirus disease 2019 (COVID-19). It has caused a significant increase in the number of cases and mortalities since its first diagnosis in December 2019. Although COVID-19 primarily affects the respiratory system, neurological involvement of the central and peripheral nervous system has been also reported. Herein, the higher risk of neurodegenerative diseases in COVID-19 patients in future is also imaginable. Neurological complications of COVID-19 infection are more commonly seen in severely ill individuals; but, earlier diagnosis and treatment can lead to better long-lasting results. In this respect, stem cell biotechnologies with considerable self-renewal and differentiation capacities have experienced great progress in the field of neurological disorders whether in finding out their underlying processes or proving them promising therapeutic approaches. Herein, many neurological disorders have been found to benefit from stem cell medicine strategies. Accordingly, in the present review, the authors are trying to discuss stem cell-based biotechnologies as promising therapeutic options for neurological disorders secondary to COVID-19 infection through reviewing neurological manifestations of COVID-19 and current stem cell-based biotechnologies for neurological disorders.

Due to the substantial burden of neurological disorders in the health, economic, and social system of society, the emergence of neurological manifestations following COVID-19 (as a life-threatening pandemic) creates the need to use efficient and modern methods of treatment. Since stem cell-based methods have been efficient for a large number of neurological diseases, it seems that the use of mentioned methods is also effective in the process of improving neurological disorders caused by COVID-19. Hereupon, the current review aims to address stem cell-based approaches as treatments showing promise to neurological disorders related to COVID-19.

• COVID-19
• Nervous system diseases
• Neurologic manifestations
• SARS-CoV-2
• Stem cell research
• Stem cells

• Purkinje cells
• cholecystokinin
• mTORC1 signaling
• neuroprotection
• spinocerebellar ataxia

• Animals
• Ataxin-1/genetics
• Ataxin-1/metabolism
• Atrophy
• Behavior, Animal/drug effects
• Calbindins/metabolism
• Chemokines, CC/agonists
• Chemokines, CC/genetics
• Chemokines, CC/metabolism
• Cholecystokinin/genetics
• Cholecystokinin/metabolism
• Disease Models, Animal
• Female
• Genetic Predisposition to Disease
• Guanine Nucleotide Exchange Factors/genetics
• Guanine Nucleotide Exchange Factors/metabolism
• Male
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Mice, Inbred C57BL
• Mice, Knockout
• Motor Activity/drug effects
• Nerve Degeneration
• Neuropeptides/genetics
• Neuropeptides/metabolism
• Purkinje Cells/drug effects
• Purkinje Cells/enzymology
• Purkinje Cells/pathology
• Signal Transduction
• Spinocerebellar Ataxias/drug therapy
• Spinocerebellar Ataxias/enzymology
• Spinocerebellar Ataxias/genetics
• Spinocerebellar Ataxias/pathology
• Tetragastrin/analogs & derivatives
• Tetragastrin/pharmacology
• Mice

• R01 NS045667 NINDS NIH HHS
• R37 NS033123 NINDS NIH HHS
• U01 NS103883 NINDS NIH HHS

• Purkinje cells
• SCA7
• cell type-specific gene deregulation
• cerebellum
• polyglutamine expansion
• retinopathy

• Animals
• Cerebellum/pathology
• Down-Regulation
• Female
• Gene Knock-In Techniques
• Male
• Mice
• Purkinje Cells/pathology
• Spinocerebellar Ataxias/pathology
• Transcriptome

Genetic variant classification is a challenge in rare adult‐onset disorders as in SCA‐PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA‐PRKCG a comprehensive phenotype description from a German multi‐center cohort, including standardized 3D MR imaging.

This cross‐sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS).

Our sample included 25 cases confirmed as SCA‐PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA‐PRKCG included slowly progressive ataxia (onset at 4–50 years), preceded in some by early‐onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive‐affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA‐PRKCG cases but in none of the controls.

In this largest cohort to date, SCA‐PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non‐ataxia movement disorders and cognitive‐affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA‐PRKCG.

• Huntington (disease)
• ataxia
• cerebellum
• chorea
• polyglutamine (polyQ) diseases

• ATXN1
• Ataxin-1
• CAG/polyglutamine disorder
• Neurodegeneration
• Repeat expansion
• SCA1
• Spinocerebellar ataxia

• Animals
• Cerebellum/pathology
• Humans
• Nuclear Proteins/genetics
• Spinocerebellar Ataxias/pathology
• Spinocerebellar Degenerations/pathology

• R21 MH119803 NIMH NIH HHS
• R01 NS083706 NINDS NIH HHS
• AG066447 NIA NIH HHS
• NS083706 NINDS NIH HHS
• 119803 NIMH NIH HHS
• R01 NS088321 NINDS NIH HHS
• NS088321 NINDS NIH HHS
• NS007224 NINDS NIH HHS
• R01 AG066447 NIA NIH HHS
• T32 NS007224 NINDS NIH HHS
• National Institute of Neurological Disorders and Stroke
• National Institute of Mental Health
• Lo Graduate Fellowship for Excellence in Stem Cell Research
• Gruber Foundation
• National Institute on Aging

Background: Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo. Methods: Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1). Results: A set of common dysregulated pathways were identified, which were utilized to construct cerebellum-specific protein-protein interaction (PPI) networks at various time-points of protein aggregation. Analysis of a SCA1 network indicated important nodes which regulate its function and might represent potential pharmacological targets. Furthermore, a set of drugs interacting with these nodes and predicted to enter the blood–brain barrier (BBB) was identified. Conclusions: Our study points to molecular mechanisms of SCA1 linked from both cellular and animal models and suggests drugs that could be tested to determine whether they affect the aggregation of pathogenic ATXN1 and SCA1 disease progression.

• ataxin-1
• blood-brain-barrier
• drugs
• network
• pathway
• polyQ

The CACNA1G gene encodes the low-voltage-activated Ca_v3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Ca_v3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Ca_v3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca²⁺ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.

• CACNA1G mutation
• deep cerebellar nuclei
• developmental and epileptic encephalopathy
• gain of function
• loss of function
• voltage-dependent T-type calcium channel

Polyglutamine spinocerebellar ataxias (polyQ SCAs) include SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and constitute a group of adult onset neurodegenerative disorders caused by the expansion of a CAG repeat sequence located within the coding region of specific genes, which translates into polyglutamine tract in the corresponding proteins. PolyQ SCAs are characterized by degeneration of the cerebellum and its associated structures and lead to progressive ataxia and other diverse symptoms. In recent years, gene and epigenetic deregulations have been shown to play a critical role in the pathogenesis of polyQ SCAs. Here, we provide an overview of the functions of wild type and pathogenic polyQ SCA proteins in gene regulation, describe the extent and nature of gene expression changes and their pathological consequences in diseases, and discuss potential avenues to further investigate converging and distinct disease pathways and to develop therapeutic strategies.

• Purkinje cells
• SCA
• epigenetic
• polyglutamine
• spinocerebellar ataxia
• transcriptional dysregulation

• ADCA
• CACNA1C
• Hereditary ataxia
• L-type calcium channel
• Mutation

• Adult
• Asian People
• Calcium Channels, L-Type/genetics
• Case-Control Studies
• Cerebellar Ataxia/genetics
• Female
• Genes, Dominant
• Humans
• Male
• Mutation
• Pedigree
• Phenotype
• Spinocerebellar Degenerations/genetics
• Young Adult

• No.20170623006TC Jilin Province Neurological Diseases Precision Medicine Science and Technology Innovation Center

• Friedrich’s ataxia MRE-11 gene
• Hereditary ataxia
• genotype
• phenotype
• spinocerebellar ataxia

Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination typically associated with cerebellar atrophy. The most prevalent SCA types are all polyQ disorders like Huntington’s disease, sharing the most relevant events in pathogenesis with this basal ganglia disorder, but with most of the damage concentrated in cerebellar neurons, and in their afferent and efferent connections (e.g., brainstem nuclei). SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB₁ receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB₂ receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB₂ receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies. The present review will address both aspects. On one hand, the endocannabinoid system becomes dysregulated in the cerebellum and also in other CNS structures (e.g., brainstem, basal ganglia) in SCAs, which may contribute to the progression of pathogenic events in these diseases. On the other hand, these endocannabinoid alterations may be pharmacologically corrected or enhanced, and this may have therapeutic consequences, either alleviating specific symptoms or eliciting neuroprotective effects, an objective presently under investigation.

• autosomal-dominant inherited ataxias
• cannabinoids
• endocannabinoid system
• motor incoordination
• neuroprotection

• Brain organoid
• Cerebellar development
• Disease modeling
• Pluripotent stem cells
• Purkinje cells
• Self-organization
• Spinocerebellar ataxia

• Animals
• Cell Differentiation
• Cerebellum/physiology
• Disease Models, Animal
• Humans
• Induced Pluripotent Stem Cells/physiology

• cacna1g
• cerebellar atrophy
• hot cross bun sign
• sca42
• spinocerebellar ataxia

• Calcium Channels, T-Type/genetics
• Family
• Female
• Genetic Predisposition to Disease
• Humans
• Middle Aged
• Mutation
• Spinocerebellar Ataxias/diagnostic imaging
• Spinocerebellar Ataxias/genetics
• Spinocerebellar Ataxias/therapy

• Genetic mechanisms
• Neurodegeneration
• Pathway analysis
• Purkinje Cell
• Spinocerebellar ataxia

• genetic network
• neurodegeneration
• spinocerebellar ataxia
• synaptic transmission
• whole exome sequencing

• Animals
• COS Cells
• Cadherins/genetics
• Chlorocebus aethiops
• E1A-Associated p300 Protein/genetics
• Exome/genetics
• Female
• Gene Regulatory Networks/genetics
• HEK293 Cells
• Humans
• Kinesins/genetics
• Male
• Pedigree
• Phospholipase D/genetics
• Plasmids
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Analysis, DNA
• Spinocerebellar Ataxias/genetics
• Transfection

The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique’s advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance.

• Cerebellum
• Neurodegenerative disease
• Ataxia
• Multiple sclerosis
• Parkinson’s disease
• Diffusion magnetic resonance imaging
• Tractography
• Volumetry
• Functional magnetic resonance imaging
• Alzheimer’s disease

• Arginine vasopressin
• Learning and memory
• Mirror water maze
• Mouse
• Spinocerebellar ataxia type 3

• Animals
• Arginine Vasopressin/metabolism
• Brain/metabolism
• Disease Models, Animal
• Machado-Joseph Disease/metabolism
• Machado-Joseph Disease/psychology
• Male
• Mice
• Spatial Learning
• Spatial Memory

• CCFS (Composite Cerebellar Functional Severity Score)
• ICARS (International Cooperative Ataxia Rating Scale)
• INAS (Inventory of Non-Ataxia Symptoms)
• SARA (Scale for the Assessment and Rating of Ataxia)
• SCAFI (SCA Functional Index)
• quality of life

• functional MRI
• magnetic susceptibility
• multiple sclerosis
• quantitative susceptibility mapping
• susceptibility tensor imaging

• Algorithms
• Animals
• Brain/metabolism
• Diffusion Magnetic Resonance Imaging/methods
• Humans
• Image Enhancement/methods
• Image Interpretation, Computer-Assisted/methods
• Reproducibility of Results
• Sensitivity and Specificity

• Bergmann glia
• Cerebellar ataxia
• EAAT
• Excitotoxicity
• Glutamate transporter
• IKK
• NF-kappaB
• Neuroinflammation
• Purkinje cell degeneration

• Animals
• Astrocytes/metabolism
• Cerebellum/metabolism
• Disease Models, Animal
• Gliosis/pathology
• I-kappa B Kinase/metabolism
• Inflammation/metabolism
• Mice, Transgenic
• NF-kappa B/metabolism
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/pathology
• Neuroglia/metabolism

• 16857 Cancer Research UK
• MR/J008060/1 Medical Research Council
• Deutsche Forschungsgemeinschaft

• Machado-Joseph disease
• autosomal-dominant inherited ataxias
• cannabinoids
• endocannabinoid signaling system
• motor incoordination
• spinocerebellar ataxia-3

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and typically associated with deficiency in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB₁ receptor (CB₁R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB₁R antagonists. Of further interest are various findings that CB₁R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse ‘ducky^2J’ model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered.

• Africa
• Burden of disease
• Capacity building
• Genetics
• Genomics
• Neurological disorders

• Africa
• Black People/genetics
• Capacity Building
• Genomics/methods
• Humans
• Nervous System Diseases/diagnosis
• Nervous System Diseases/ethnology
• Nervous System Diseases/genetics
• Nervous System Diseases/therapy

• G1100540 Medical Research Council
• G0900652 Medical Research Council
• U54 HG007479 NHGRI NIH HHS
• G0400074 Medical Research Council
• G0502157 Medical Research Council

Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research.

• ataxia
• cerebellum
• induced pluripotent stem cells
• neurodegenerative disease