Proteome Homeostasis Dysfunction: A Unifying Principle in ALS Pathogenesis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no effective treatments.
• Proteome homeostasis, the balance of protein production and degradation, is increasingly implicated in ALS.
• Genetic mutations in ALS are hypothesized to disrupt this delicate proteostasis.

Purpose of the Study:

• To propose a unifying hypothesis for ALS pathogenesis based on proteome imbalance.
• To explore the widespread impact of genetic lesions on the entire proteome in ALS.
• To suggest that proteostasis network stratification may guide ALS therapeutic development.

Main Methods:

• Hypothesis generation based on existing evidence of proteostasis in ALS.
• Analysis of the proposed widespread impact of genetic lesions on protein homeostasis.
• Conceptual framework for stratifying ALS patients based on proteostasis network characteristics.

Main Results:

• Genetic lesions in ALS, including those in mRNA-binding proteins, are hypothesized to cause significant, widespread proteome imbalance.
• This imbalance is not limited to specific proteins but affects the entire proteome.
• Proteome imbalance can lead to functional deficits like altered excitability and eventual cell death.

Conclusions:

• A unifying principle for ALS pathogenesis is proposed: widespread proteome imbalance.
• The impact of ALS-associated genetic mutations is systemic, affecting the entire proteome.
• Stratification of ALS based on proteostasis network status may be crucial for developing targeted and effective therapies.