scholarly journals Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
So Yoen Choi ◽  
Ju-Hyun Lee ◽  
Ah-Young Chung ◽  
Youhwa Jo ◽  
Joo-ho Shin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Protein Phosphatase ◽  
Molecular Mechanisms ◽  
Protein Phosphatase 1 ◽  
Mitochondrial Morphology ◽  
Pathological Features ◽  
Primary Neuronal Culture ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Spatiotemporal Dynamics of Molecular Pathology in Amyotrophic Lateral Sclerosis

2018 ◽  
Author(s):  
Silas Maniatis ◽  
Tarmo Äijö ◽  
Sanja Vickovic ◽  
Catherine Braine ◽  
Kristy Kang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Early Time ◽  
Spatiotemporal Dynamics ◽  
Course Of Disease ◽  
Molecular Events ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractParalysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify novel pathway dynamics, regional differences between microglia and astrocyte populations at early time-points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.One Sentence SummaryAnalysis of the ALS spinal cord using Spatial Transcriptomics reveals spatiotemporal dynamics of disease driven gene regulation.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

scholarly journals Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. 89-93 ◽  
Author(s):  
Silas Maniatis ◽  
Tarmo Äijö ◽  
Sanja Vickovic ◽  
Catherine Braine ◽  
Kristy Kang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Early Time ◽  
Course Of Disease ◽  
Molecular Events ◽  
Motor Neuron Loss ◽  
Als Patients ◽  
Lateral Sclerosis

Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.

scholarly journals Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiaki Furukawa
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Wild Type ◽  
Sporadic Als ◽  
Familial Form ◽  
Recent Developments ◽  
Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

scholarly journals Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Iris-Stefania Pasniceanu ◽  
Manpreet Singh Atwal ◽  
Cleide Dos Santos Souza ◽  
Laura Ferraiuolo ◽  
Matthew R. Livesey
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Repeat Expansion ◽  
Neuronal Function ◽  
Repeat Expansion Mutation ◽  
Expansion Mutation ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

scholarly journals A streamlined CRISPR workflow to introduce mutations and generate isogenic iPSCs for modeling amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Eric Deneault ◽  
Mathilde Chaineau ◽  
Maria Jose Castellanos-Montiel ◽  
Anna Kristyna Franco Flores ◽  
Ghazal Haghi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Control Line ◽  
Human Neurons ◽  
Recent Developments ◽  
Induced Pluripotent ◽  
Specific Contribution ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) represents a complex neurodegenerative disorder with significant genetic heterogeneity. To date, both the genetic etiology and the underlying molecular mechanisms driving this disease remain poorly understood, although in recent years a number of studies have highlighted a number of genetic mutations causative for ALS. With these mutations pointing to potential pathways that may be affected within individuals with ALS, having the ability to generate human neurons and other disease relevant cells containing these mutations becomes even more critical if new therapies are to emerge. Recent developments with the advent of induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing fields gave us the tools to introduce or correct a specific mutation at any site within the genome of an iPSC, and thus model the specific contribution of risk mutations. In this study we describe a rapid and efficient way to either introduce a mutation into a control line, or to correct a mutation, generating an isogenic control line from patient-derived iPSCs with a given mutation. The mutations introduced were the G93A mutation into SOD1 or H517Q into FUS, and the mutation corrected was a patient iPSC line with I114T in SOD1. A combination of small molecules and growth factors were used to guide a stepwise differentiation of the edited cells into motor neurons in order to demonstrate that disease-relevant cells could be generated for downstream applications. Through a combination of iPSCs and CRISPR editing, the cells generated here will provide fundamental insights into the molecular mechanisms underlying neuron degeneration in ALS.

scholarly journals Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2413
Author(s):  
Azin Amin ◽  
Nirma D. Perera ◽  
Philip M. Beart ◽  
Bradley J. Turner ◽  
Fazel Shabanpoor
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Protein Aggregate ◽  
In Vivo Models ◽  
Primary Stress ◽  
Lateral Sclerosis

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

scholarly journals MFN2 Influences Amyotrophic Lateral Sclerosis Pathology

2021 ◽  
Author(s):  
Kristi Russell ◽  
Jonathan M. Downie ◽  
Summer Gibson ◽  
Patty Figueroa ◽  
Cody J Steely ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Potential ◽  
Sequence Data ◽  
Mitochondrial Morphology ◽  
University Of Utah ◽  
Morphological Defects ◽  
The University ◽  
Lateral Sclerosis

Objective: To better understand the pathology of amyotrophic lateral sclerosis, we used sequence data from patients seen at the University of Utah to identify novel disease-associated loci. We utilized both in vitro and in vivo studies to determine the biological effect of patient mutations in MFN2. Methods: Sequence data for a total of 140 patients were run through VAAST and Phevor to determine genes that were more burdened with rare, nonsynonymous variants compared to control longevity cohort. Variants identified in MFN2 were expressed in Mfn2 knockout cells to determine if mutant MFN2 could rescue mitochondrial morphology defects. We identified additional rare, nonsynonymous variants in MFN2 in ALSdb that were expressed in knockout mouse embryonic fibroblasts (MEFs). Membrane potential was measured to quantify mitochondrial health upon mutant MFN2 expression. mfn2 knockout zebrafish were used to examine movement compared to wildtype and protein aggregation in brain. Results: MFN2 mutations identified in ALS patients from our University of Utah cohort and ALSdb were defective in rescuing morphological defects in Mfn2 knockout MEFs. Selected mutants showed decreased membrane potential compared to wildtype MFN2 expression. Zebrafish heterozygous and homozygous for loss of mfn2 showed increased TDP-43 levels in their hindbrain and cerebellum. Conclusion: In total, 21 rare, deleterious mutations in MFN2 were tested in Mfn2 knockout MEFs. Mutant MFN2 expression was not able to rescue the knockout phenotype, though at differing degrees of severity. Decreased membrane potential also argues for inhibited mitochondrial function. Increased TDP-43 levels in mutant zebrafish illustrates MFN2's function in ALS pathology. MFN2 variants influence ALS pathology and highlight the importance of mitochondria in neurodegeneration.

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