Aggregation-Prone Pathogenic SOD1 Variants in Amyotrophic Lateral Sclerosis: Insights from Computational Genomics and...

Area of Science:

• Genomics
• Neuroscience
• Biochemistry

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown causes.
• Mutations in the SOD1 gene are linked to familial ALS (fALS) and cause toxic gain-of-function via protein misfolding and aggregation.
• Understanding SOD1 mutations is crucial for ALS pathogenesis research.

Purpose of the Study:

• To systematically analyze 244 SOD1 missense mutations using computational tools.
• To identify mutations associated with SOD1 misfolding, aggregation, and pathogenicity.
• To provide mechanistic insights into SOD1 dysfunction in ALS.

Main Methods:

• Utilized a multi-tiered computational framework combining structural, functional, and pathogenic predictors.
• Employed sequence-based (SIFT, PolyPhen-2, FATHMM) and structure-guided (mCSM, PremPS, DynaMut2) tools.
• Assessed aggregation propensity using SODA analysis and protein-protein interaction networks.

Main Results:

• Identified 79 destabilizing SOD1 mutations, with 64 classified as pathogenic.
• Pinpointed eight aggregation-prone mutations (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I), including H72Y which disrupts a critical zinc-binding residue.
• Linked SOD1 to oxidative stress and protein homeostasis pathways via network analysis.

Conclusions:

• Computational genomics effectively identifies mutation-driven SOD1 dysfunction in ALS.
• Mechanistic insights into SOD1 aggregation provide a basis for developing targeted therapeutic strategies.
• Focusing on aggregation-prone variants may offer new avenues for ALS treatment.