Senolytics: A Novel Strategy for Neuroprotection in ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

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Progress in Clinical Neurosciences: The Evidence for ALS as a Multisystems Disorder of Limited Phenotypic Expression

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100001505 ◽

2001 ◽

Vol 28 (4) ◽

pp. 283-298 ◽

Cited By ~ 48

Author(s):

Michael J. Strong

Keyword(s):

Motor Neurons ◽

Phenotypic Variability ◽

Phenotypic Expression ◽

Disease Process ◽

Cellular Level ◽

Central Component ◽

Biological Processes ◽

Motor Neuron Degeneration ◽

Biological Heterogeneity ◽

Lateral Sclerosis

Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.

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Nutrient Effects on Motor Neurons and the Risk of Amyotrophic Lateral Sclerosis

Nutrients ◽

10.3390/nu13113804 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3804

Author(s):

Polina S. Goncharova ◽

Tatiana K. Davydova ◽

Tatiana E. Popova ◽

Maxim A. Novitsky ◽

Marina M. Petrova ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Randomized Clinical Trials ◽

Progression Rate ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Vitamin B9 ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression. Methods: We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010–2020. Discussion: We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development. Conclusion: The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.

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A microfluidic approach to rescue ALS motor neuron degeneration using rapamycin

Scientific Reports ◽

10.1038/s41598-021-97405-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Phaneendra Chennampally ◽

Ambreen Sayed-Zahid ◽

Prabakaran Soundararajan ◽

Jocelyn Sharp ◽

Gregory A. Cox ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Motor Neuron ◽

Motor Neurons ◽

Embryonic Stem ◽

Immunosuppressive Drug ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Lateral Sclerosis

AbstractTAR DNA-binding protein-43 (TDP-43) is known to accumulate in ubiquitinated inclusions of amyotrophic lateral sclerosis affected motor neurons, resulting in motor neuron degeneration, loss of motor functions, and eventually death. Rapamycin, an mTOR inhibitor and a commonly used immunosuppressive drug, has been shown to increase the survivability of Amyotrophic Lateral Sclerosis (ALS) affected motor neurons. Here we present a transgenic, TDP-43-A315T, mouse model expressing an ALS phenotype and demonstrate the presence of ubiquitinated cytoplasmic TDP-43 aggregates with > 80% cell death by 28 days post differentiation in vitro. Embryonic stem cells from this mouse model were used to study the onset, progression, and therapeutic remediation of TDP-43 aggregates using a novel microfluidic rapamycin concentration gradient generator. Results using a microfluidic device show that ALS affected motor neuron survival can be increased by 40.44% in a rapamycin dosage range between 0.4-1.0 µM.

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Targeting Macrophage for the Treatment of Amyotrophic Lateral Sclerosis

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190409103831 ◽

2019 ◽

Vol 18 (5) ◽

pp. 366-371 ◽

Cited By ~ 1

Author(s):

Lian Li ◽

Jie Liu ◽

Hua She

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Neuromuscular Junction ◽

Motor Neurons ◽

Macrophage Activation ◽

Early Event ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

The Brain ◽

Lateral Sclerosis

Background & Objective: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that specifically affects motor neurons in the brain and in the spinal cord. Patients with amyotrophic lateral sclerosis usually die from respiratory failure within 3 to 5 years from when the symptoms first appear. Currently, there is no cure for amyotrophic lateral sclerosis. Accumulating evidence suggests that dismantling of neuromuscular junction is an early event in the pathogenesis of amyotrophic lateral sclerosis. Conclusion: It is starting to realized that macrophage malfunction contributes to the disruption of neuromuscular junction. Modulation of macrophage activation states may stabilize neuromuscular junction and provide protection against motor neuron degeneration in amyotrophic lateral sclerosis.

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The Motor Neuron Degeneration (mnd) Gene Acts Intrinsically in Motor Neurons and Peripheral Fibroblasts

Molecular and Cellular Neuroscience ◽

10.1006/mcne.1997.0617 ◽

1997 ◽

Vol 9 (3) ◽

pp. 185-193 ◽

Cited By ~ 3

Author(s):

Joanne C. Porter ◽

Anne Messer ◽

Alan Peterson

Keyword(s):

Motor Neuron ◽

Motor Neurons ◽

Motor Neuron Degeneration ◽

Neuron Degeneration

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Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)

Brain Sciences ◽

10.3390/brainsci8120212 ◽

2018 ◽

Vol 8 (12) ◽

pp. 212 ◽

Cited By ~ 4

Author(s):

Darija Šoltić ◽

Melissa Bowerman ◽

Joanne Stock ◽

Hannah Shorrock ◽

Thomas Gillingwater ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Spinal Muscular Atrophy ◽

Calcium Binding ◽

Bioinformatics Analysis ◽

Muscular Atrophy ◽

Molecular Pathways ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Therapeutic Development ◽

Lateral Sclerosis

Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport—both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases.

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