Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by a progressive paralysis due to the loss of particular neurons in our nervous system called motor neurons, that exert voluntary control of all our skeletal muscles. It is not entirely understood why motor neurons are particularly vulnerable in ALS, neither is it completely clear why certain groups of motor neurons, including those that regulate eye movement, are rather resilient to this disease. However, both vulnerability and resilience to ALS likely reflect cell intrinsic properties of different motor neuron subpopulations as well as non-cell autonomous events regulated by surrounding cell types. In this review we dissect the particular properties of different motor neuron types and their responses to disease that may underlie their respective vulnerabilities and resilience. Disease progression in ALS involves multiple cell types that are closely connected to motor neurons and we here also discuss their contributions to the differential vulnerability of motor neurons.

Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading to spasticity, muscle atrophy, and paralysis. ALS involves several disease stages, and multiple cell types show dysfunction and play important roles during distinct phases of disease initiation and progression, subsequently leading to selective MN loss. Why MNs are particularly vulnerable in this lethal disease is still not entirely clear. Neither is it fully understood why certain MNs are more resilient to degeneration in ALS than others. Brain stem MNs of cranial nerves III, IV, and VI, which innervate our eye muscles, are highly resistant and persist until the end-stage of the disease, enabling paralyzed patients to communicate through ocular tracking devices. MNs of the Onuf’s nucleus in the sacral spinal cord, that innervate sphincter muscles and control urogenital functions, are also spared throughout the disease. There is also a differential vulnerability among MNs that are intermingled throughout the spinal cord, that directly relate to their physiological properties. Here, fast-twitch fatigable (FF) MNs, which innervate type IIb muscle fibers, are affected early, before onset of clinical symptoms, while slow-twitch (S) MNs, that innervate type I muscle fibers, remain longer throughout the disease progression. The resilience of particular MN subpopulations has been attributed to intrinsic determinants and multiple studies have demonstrated their unique gene regulation and protein content in health and in response to disease. Identified factors within resilient MNs have been utilized to protect more vulnerable cells. Selective vulnerability may also, in part, be driven by non-cell autonomous processes and the unique surroundings and constantly changing environment close to particular MN groups. In this article, we review in detail the cell intrinsic properties of resilient and vulnerable MN groups, as well as multiple additional cell types involved in disease initiation and progression and explain how these may contribute to the selective MN resilience and vulnerability in ALS.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.

• amyotrophic lateral sclerosis
• frontotemporal dementia
• iPSC
• motor neuron
• neurodegeneration

• ALS
• Fast and slow motor units
• Neurodegeneration
• Neuromuscular junction
• Oculomotor neuron
• Selective vulnerability

• AMPA receptor
• Amyotrophic lateral sclerosis
• Calcium homeostasis
• Gene-environment (GxE) interaction
• Glutamate
• Methylmercury

• Amyotrophic Lateral Sclerosis/chemically induced
• Amyotrophic Lateral Sclerosis/physiopathology
• Calcium
• Free Radical Scavengers
• Gene-Environment Interaction
• Glutamic Acid
• Humans
• Methylmercury Compounds/toxicity
• Receptors, AMPA
• Superoxide Dismutase/toxicity

• R01 ES024064 NIEHS NIH HHS
• T32 ES007255 NIEHS NIH HHS

• Amyotrophic lateral sclerosis
• Astrocytes
• Biomarker
• GFAP
• Motor neuron disease

Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments.

• Synapses
• Neurotransmission
• In vitro techniques
• Induced pluripotent stem cells
• Neuronal networks
• Neurogenesis
• Neural stem cells
• Embryonic stem cells
• Induced neurons

• Amyotrophic lateral sclerosis
• Cell therapy
• Clinical trial
• Motor neuron
• Stem cell
• Transplantation

Neurodegenerative disorders are characterized by the selective vulnerability and progressive loss of discrete neuronal populations. Non-neuronal cells appear to significantly contribute to neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS), Parkinson, and Alzheimer’s disease. In ALS, there is deterioration of motor neurons in the cortex, brainstem, and spinal cord, which control voluntary muscle groups. This results in muscle wasting, paralysis, and death. Neuroinflammation, characterized by the appearance of reactive astrocytes and microglia as well as macrophage and T-lymphocyte infiltration, appears to be highly involved in the disease pathogenesis, highlighting the involvement of non-neuronal cells in neurodegeneration. There appears to be cross-talk between motor neurons, astrocytes, and immune cells, including microglia and T-lymphocytes, which are subsequently activated. Currently, effective therapies for ALS are lacking; however, the non-cell autonomous nature of ALS may indicate potential therapeutic targets. Here, we review the mechanisms of action of astrocytes, microglia, and T-lymphocytes in the nervous system in health and during the pathogenesis of ALS. We also evaluate the therapeutic potential of these cellular populations, after transplantation into ALS patients and animal models of the disease, in modulating the environment surrounding motor neurons from pro-inflammatory to neuroprotective. We also thoroughly discuss the recent advances made in the field and caveats that need to be overcome for clinical translation of cell therapies aimed at modulating non-cell autonomous events to preserve remaining motor neurons in patients.

• Amyotrophic Lateral Sclerosis/immunology
• Amyotrophic Lateral Sclerosis/pathology
• Amyotrophic Lateral Sclerosis/therapy
• Animals
• Astrocytes/metabolism
• Astrocytes/transplantation
• COS Cells
• Cell- and Tissue-Based Therapy/methods
• Chlorocebus aethiops
• Disease Models, Animal
• Humans
• Inflammation/immunology
• Inflammation/therapy
• Macrophages/immunology
• Mice
• Microglia/metabolism
• Microglia/transplantation
• Motor Neurons/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation

• Biomedical Research
• Humans
• Induced Pluripotent Stem Cells/cytology
• Neurodegenerative Diseases/physiopathology
• Neurodegenerative Diseases/therapy