scholarly journals Valosin-containing protein regulates the stability of amyotrophic lateral sclerosis-causing fused in sarcoma granules in cells by changing ATP concentrations inside the granules

2021 ◽  
Author(s):  
Kyota Yasuda ◽  
Tomonobu M. Watanabe ◽  
Myeong-Gyun Kang ◽  
Jeong Kon Seo ◽  
Hyun-Woo Rhee ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Atpase Activity ◽  
De Novo ◽  
Proteomics Analysis ◽  
Fused In Sarcoma ◽  
The Stability ◽  
Microscopy Images ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation ◽  
In Cells

Fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) to form granules in cells, leading to pathogenic aggregations that cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Proteomics analysis revealed that FUS granules contain valosin-containing protein (VCP), a member of the AAA family ATPase. Confocal microscopy images showed that VCP co-localized in the FUS granules in cells. This study demonstrates that VCP in granules has a two-faced role in FUS granulation: VCP stabilizes de novo FUS granules, while VCP present in the granules for extended periods dissolves them. This VCP function relies on its ATPase activity to consume ATP in granules. VCP stabilizes de novo FUS by reducing intragranular ATP concentrations to a range below the cytosolic concentration. VCP continually consumes ATP during its stay in the granules, which eventually lowers ATP concentrations to a range that destabilizes the granules. VCP, therefore, acts as a timer to limit the residence of FUS granules in cells and thereby prohibits the FUS fibrillization that occurs in persistent granules. VCP ATPase activity plays a role in FUS granule turnover.

scholarly journals Role and therapeutic potential of liquid‒liquid phase separation in amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Donya Pakravan ◽  
Gabriele Orlando ◽  
Valérie Bercier ◽  
Ludo Van Den Bosch
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Phase Separation ◽  
Liquid Phase ◽  
Therapeutic Potential ◽  
Liquid Phase Separation ◽  
Disordered Proteins ◽  
Familial Als ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Liquid Liquid Phase Separation

Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess ‘low-complexity domains’ (LCDs) and are considered as ‘intrinsically disordered proteins’ (IDPs), which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional ‘liquid‒liquid phase separation’ (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.

Cytoplasmic TDP-43 accumulation in cells of the adrenal medulla in individuals with or without amyotrophic lateral sclerosis

2014 ◽  
Vol 34 (6) ◽  
pp. 535-540
Author(s):  
Koichi Okamoto ◽  
Masakuni Amari ◽  
Yukio Fujita ◽  
Kouki Makioka ◽  
Toshio Fukuda ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Adrenal Medulla ◽  
Lateral Sclerosis ◽  
In Cells

scholarly journals Pathogenicity of exonic indels in fused in sarcoma in amyotrophic lateral sclerosis

2012 ◽  
Vol 33 (2) ◽  
pp. 424.e23-424.e24 ◽  
Author(s):  
Nicola J. Rutherford ◽  
Nicole A. Finch ◽  
Mariely DeJesus-Hernandez ◽  
Richard J.P. Crook ◽  
Catherine Lomen-Hoerth ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Fused In Sarcoma ◽  
Lateral Sclerosis

Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis

2011 ◽  
Vol 39 (5) ◽  
pp. 1482-1487 ◽  
Author(s):  
Emma L. Bastow ◽  
Campbell W. Gourlay ◽  
Mick F. Tuite
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Basis ◽  
Protein Misfolding ◽  
Model Organism ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mutant Sod1 ◽  
Fused In Sarcoma ◽  
Functional Inactivation ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.

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