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

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).

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Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations

Neuromuscular Disorders ◽

10.1016/s0960-8966(00)00215-7 ◽

2001 ◽

Vol 11 (4) ◽

pp. 404-410 ◽

Cited By ~ 30

Author(s):

C. Gellera ◽

B. Castellotti ◽

M.C. Riggio ◽

V. Silani ◽

L. Morandi ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Gene Mutations ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Missense Mutations ◽

Superoxide Dismutase Gene ◽

Lateral Sclerosis

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Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation

10.1101/2021.04.30.442163 ◽

2021 ◽

Author(s):

Lara Gruijs da Silva ◽

Francesca Simonetti ◽

Saskia Hutten ◽

Henrick Riemenschneider ◽

Erin L. Sternburg ◽

...

Keyword(s):

Phase Separation ◽

Neurodegenerative Disorders ◽

Nuclear Import ◽

Cellular Response ◽

Rna Binding ◽

Low Complexity ◽

Post Translational Modifications ◽

Multi Scale ◽

Regulatory Functions ◽

Lateral Sclerosis

AbstractPost-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the RNA-binding protein TDP-43, is hyperphosphorylated in disease on several C-terminal serine residues, which is generally believed to promote TDP-43 aggregation. Here, we show that hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduce TDP-43 phase separation and aggregation and render TDP-43 condensates more liquid-like and dynamic. Multi-scale simulations reveal reduced homotypic interactions of TDP-43 low complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We propose that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

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Faculty Opinions recommendation of Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12796962.14073060 ◽

2011 ◽

Author(s):

Guy Rouleau

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

Journal of International Medical Research ◽

10.1177/03000605211033219 ◽

2021 ◽

Vol 49 (7) ◽

pp. 030006052110332

Author(s):

Zhiliang Fan ◽

Hong Jiang ◽

Xueqin Song ◽

Yansu Guo ◽

Xinying Tian

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Healthy Subjects ◽

Chinese Population ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Glutathione S Transferase ◽

Genotype Frequencies ◽

Sporadic Als ◽

Increased Risk ◽

Chi Squared ◽

Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

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