Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives

Area of Science:

• Neurodegenerative diseases
• Molecular biology
• Genetics

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration.
• Protein aggregation, involving TDP-43, SOD1, FUS, and C9orf72-derived dipeptide repeat proteins (DPRs), is a central pathological hallmark.
• These proteins aggregate and spread via prion-like mechanisms, contributing to disease progression.

Purpose of the Study:

• To elucidate the role of protein aggregation in ALS pathogenesis.
• To understand the mechanisms by which pathogenic proteins disrupt cellular functions.
• To explore the interplay between protein aggregation, RNA metabolism, and cellular stress responses in ALS.

Main Methods:

• Review of existing literature on ALS pathogenesis.
• Analysis of the molecular mechanisms of key pathogenic proteins (TDP-43, SOD1, FUS, DPRs).
• Investigation of cellular responses and stress pathways involved in ALS.

Main Results:

• TDP-43 proteinopathy disrupts RNA processing, protein transport, and DNA repair.
• SOD1 and FUS mutations promote toxic aggregation, impairing cellular homeostasis.
• C9orf72-derived DPRs interfere with nucleocytoplasmic transport, and protein aggregates propagate between cells.
• Mitochondrial dysfunction, oxidative stress, and impaired DNA repair contribute to ALS pathogenesis.
• Cellular protective mechanisms are often overwhelmed in ALS.

Conclusions:

• Protein aggregation is a critical driver of ALS, affecting multiple cellular pathways.
• Understanding the complex interplay of proteinopathy, RNA metabolism, and cellular stress is essential for ALS therapy.
• Targeting misfolded proteins offers promising therapeutic avenues for ALS treatment.