scholarly journals Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond

2009 ◽  
Vol 187 (6) ◽  
pp. 761-772 ◽  
Author(s):  
Hristelina Ilieva ◽  
Magdalini Polymenidou ◽  
Don W. Cleveland
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorders ◽  
Cell Types ◽  
Neuronal Dysfunction ◽  
Inherited Disease ◽  
Supporting Cells ◽  
Cerebellar Ataxias ◽  
Multiple Cell ◽  
Lateral Sclerosis ◽  
Human Neurodegenerative Disease

Selective degeneration and death of one or more classes of neurons is the defining feature of human neurodegenerative disease. Although traditionally viewed as diseases mainly affecting the most vulnerable neurons, in most instances of inherited disease the causative genes are widely—usually ubiquitously—expressed. Focusing on amyotrophic lateral sclerosis (ALS), especially disease caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1), we review here the evidence that it is the convergence of damage developed within multiple cell types, including within neighboring nonneuronal supporting cells, which is crucial to neuronal dysfunction. Damage to a specific set of key partner cells as well as to vulnerable neurons may account for the selective susceptibility of neuronal subtypes in many human neurodegenerative diseases, including Huntington's disease (HD), Parkinson's disease (PD), prion disease, the spinal cerebellar ataxias (SCAs), and Alzheimer's disease (AD).

scholarly journals Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?

2020 ◽  
Vol 21 (21) ◽  
pp. 7923
Author(s):  
Giada Cipollina ◽  
Arash Davari Serej ◽  
Gianluca Di Nolfi ◽  
Andrea Gazzano ◽  
Andrea Marsala ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neuronal Damage ◽  
Cell Types ◽  
Microglia Cell ◽  
Cell Responses ◽  
The Past ◽  
Single Drug ◽  
Multiple Cell ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a complex pathology: (i) the neurodegeneration is chronic and progressive; it starts focally in specific central nervous system (CNS) areas and spreads to different districts; (ii) multiple cell types further than motor neurons (i.e., glial/immune system cells) are actively involved in the disease; (iii) both neurosupportive and neurotoxic neuroinflammatory responses were identified. Microglia cells (a key player of neuroinflammation in the CNS) attracted great interest as potential target cell population that could be modulated to counteract disease progression, at least in preclinical ALS models. However, the heterogeneous/multifaceted microglia cell responses occurring in different CNS districts during the disease represent a hurdle for clinical translation of single-drug therapies. To address this issue, over the past ten years, several studies attempted to dissect the complexity of microglia responses in ALS. In this review, we shall summarize these results highlighting how the heterogeneous signature displayed by ALS microglia reflects not only the extent of neuronal demise in different regions of the CNS, but also variable engagement in the attempts to cope with the neuronal damage. We shall discuss novel avenues opened by the advent of single-cell and spatial transcriptomics technologies, underlining the potential for discovery of novel therapeutic targets, as well as more specific diagnostic/prognostic not-invasive markers of neuroinflammation.

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Elise Liu ◽  
Léa Karpf ◽  
Delphine Bohl
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Frontotemporal Dementia ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Induced Pluripotent ◽  
Different Cell Types ◽  
Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

scholarly journals Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

2021 ◽  
Author(s):  
Wouter van Rheenen ◽  
Rick A.A. van der Spek ◽  
Mark K. Bakker ◽  
Joke J.F.A. van Vugt ◽  
Paul J. Hop ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rare Variants ◽  
Unmet Need ◽  
Life Time ◽  
Cell Types ◽  
Brain Regions ◽  
Multiple Traits ◽  
Association Analyses ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

scholarly journals Nucleolin Rescues TDP-43 Toxicity in Yeast and Human Cell Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Caterina Peggion ◽  
Maria Lina Massimino ◽  
Roberto Stella ◽  
Raissa Bortolotto ◽  
Jessica Agostini ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Viability ◽  
Human Cell ◽  
Neurodegenerative Disorders ◽  
Nuclear Protein ◽  
Human Cells ◽  
Cell Models ◽  
Nuclear Retention ◽  
Beneficial Effects ◽  
Lateral Sclerosis

TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may be promising therapeutic targets for TDP-43 proteinopathies. Here we show by the use of refined yeast models that the nucleolar protein nucleolin (NCL) acts as a potent suppressor of TDP-43 toxicity, restoring cell viability. We provide evidence that NCL co-expression is able to alleviate TDP-43-induced damage also in human cells, further supporting its beneficial effects in a more consistent pathophysiological context. Presented data suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.

scholarly journals Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 901 ◽  
Author(s):  
Elena Obrador ◽  
Rosario Salvador ◽  
Rafael López-Blanch ◽  
Ali Jihad-Jebbar ◽  
Soraya L. Vallés ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Cell Types ◽  
T Cell Subsets ◽  
Cellular Interactions ◽  
Underlying Mechanisms ◽  
Different Cell Types ◽  
And Oxidative Stress ◽  
Different Levels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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 Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins

2019 ◽  
Vol 28 (R2) ◽  
pp. R187-R196 ◽  
Author(s):  
Michael Fernandopulle ◽  
GuoZhen Wang ◽  
Jonathon Nixon-Abell ◽  
Seema Qamar ◽  
Varun Balaji ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Recent Work ◽  
Neurodegenerative Disorders ◽  
Low Complexity ◽  
Present Review ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Missense Mutations ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Lateral Sclerosis

Abstract Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

Sign in / Sign up

Export Citation Format

Share Document