Proteostasis disturbance in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motoneuron loss.
• Abnormal protein aggregation and impaired proteostasis are hallmarks of both sporadic and familial ALS.
• The proteostasis network regulates protein synthesis, folding, trafficking, secretion, and degradation.

Purpose of the Study:

• To explore the role of the proteostasis network in ALS pathogenesis.
• To investigate the contribution of endoplasmic reticulum (ER) dysfunction to motoneuron degeneration in ALS.
• To identify potential therapeutic targets within the proteostasis network for ALS treatment.

Main Methods:

• Review of functional studies in various ALS models.
• Analysis of proteostasis network components and their impact on disease progression.
• Examination of ER folding capacity alterations in ALS pathogenesis.

Main Results:

• Dysregulation of the proteostasis network, with varied effects depending on the targeted component, is observed in ALS models.
• Impaired endoplasmic reticulum (ER) folding capacity is an early defect in ALS, contributing to motoneuron dysfunction and denervation.
• Targeting specific proteostasis network modules shows promise in preclinical studies.

Conclusions:

• Alterations in the proteostasis network, especially ER dysfunction, are central to ALS pathology.
• Therapeutic strategies targeting the proteostasis network, including small molecules and gene therapy, represent promising avenues for ALS intervention.
• Further research into proteostasis network modulation could lead to treatments to delay or halt ALS progression.