scholarly journals Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2247
Author(s):  
Yi Zhang ◽  
Jiayu Gu ◽  
Qiming Sun
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Phase Separation ◽  
Gene Mutations ◽  
Stress Granules ◽  
Protein Aggregates ◽  
Toxic Protein ◽  
Selective Autophagy ◽  
Dynamic Assembly ◽  
Autophagy Pathway ◽  
Lateral Sclerosis

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

scholarly journals Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease

2019 ◽  
Author(s):  
Richard J. Wheeler ◽  
Hyun O. Lee ◽  
Ina Poser ◽  
Arun Pal ◽  
Thom Doeleman ◽  
...  
Keyword(s):  
Phase Separation ◽  
Neurodegenerative Disease ◽  
Stress Granules ◽  
Life Time ◽  
Stress Granule ◽  
Phase Behaviour ◽  
Granule Proteins ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with few avenues for treatment. Many proteins implicated in ALS associate with stress granules, which are examples of liquid-like compartments formed by phase separation. Aberrant phase transition of stress granules has been implicated in disease, suggesting that modulation of phase transitions could be a possible therapeutic route. Here, we combine cell-based and protein-based screens to show that lipoamide, and its related compound lipoic acid, reduce the propensity of stress granule proteins to aggregate in vitro. More significantly, they also prevented aggregation of proteins over the life time of Caenorhabditis elegans. Observations that they prevent dieback of ALS patient-derived (FUS mutant) motor neuron axons in culture and recover motor defects in Drosophila melanogaster expressing FUS mutants suggest plausibility as effective therapeutics. Our results suggest that altering phase behaviour of stress granule proteins in the cytoplasm could be a novel route to treat ALS.

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.

SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modeling

2013 ◽  
Vol 47 (5) ◽  
pp. 751-757 ◽  
Author(s):  
E. V. Lysogorskaia ◽  
A. V. Rossokhin ◽  
N. Yu. Abramycheva ◽  
M. N. Zakharova ◽  
S. N. Illarioshkin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Molecular Modeling ◽  
Gene Mutations ◽  
Sod1 Gene ◽  
Lateral Sclerosis

scholarly journals Paraoxonase gene mutations in amyotrophic lateral sclerosis

2010 ◽  
Vol 68 (1) ◽  
pp. 102-107 ◽  
Author(s):  
Nicola Ticozzi ◽  
Ashley Lyn LeClerc ◽  
Pamela J. Keagle ◽  
Jonathan D. Glass ◽  
Anne-Marie Wills ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Gene Mutations ◽  
Lateral Sclerosis

SOD1 gene mutations in Italian patients with Sporadic Amyotrophic Lateral Sclerosis (ALS)

2006 ◽  
Vol 16 (11) ◽  
pp. 800-804 ◽  
Author(s):  
L. Corrado ◽  
S. D’Alfonso ◽  
L. Bergamaschi ◽  
L. Testa ◽  
M. Leone ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Gene Mutations ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Sod1 Gene ◽  
Lateral Sclerosis

scholarly journals Development of new tools to study lipidated mammalian ATG8

2021 ◽  
Author(s):  
Sang-Won Park ◽  
Pureum Jeon ◽  
Akinori Yamasaki ◽  
Hye Eun Lee ◽  
Ji Young Mun ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Light Chain ◽  
Functional Significance ◽  
Aminobutyric Acid ◽  
Acid Receptor ◽  
Receptor Associated Protein ◽  
Selective Autophagy ◽  
Selective Interaction ◽  
Available Information ◽  
Lateral Sclerosis

Abstract Mammals conserve multiple mammalian ATG8 proteins (mATG8s) consisting of γ-aminobutyric acid receptor-associated protein (GABARAP) and microtubule-associated protein 1 light-chain 3 (LC3) subfamilies that tightly bind to the autophagic membranes in a lipidated form. They are crucial in selective autophagy and recruit proteins bearing LC3-interacting region (LIR) motifs. However, because limited research tools are available, information about the specific roles of each lipidated mATG8 in selective autophagy is scarce. Here, we identified LIR motifs specific to the lipidated form of each mATG8 and characterized the residues critical for their selective interaction using cell-based assays and structural analyses. Then, we used these selective LIR motifs to develop probes and irreversible deconjugases that targeted selective lipidated mATG8s in the autophagic membrane, revealing that lipidated GABARAP subfamily proteins regulate aggrephagy of amyotrophic lateral sclerosis-linked protein aggregates. Our tools will be useful in elucidating the functional significance of each mATG8 protein in autophagy research.

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