Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
• Vesicle-associated membrane protein-associated protein-B (VAPB) mutations, particularly P56S, are linked to familial ALS.
• The precise mechanisms by which VAPB mutations cause motor neuron (MN) dysfunction are not fully understood.

Approach:

• Utilized inducible wild-type (WT) and VAPB P56S mutant expressing iPSC-derived motor neurons (MNs).
• Assessed neuronal firing, mitochondrial-ER contact (MERC), mitochondrial membrane potential (MMP), and endoplasmic reticulum (ER) stress responses.
• Investigated the Integrated Stress Response (ISR) pathway, including ATF4 expression and protein synthesis.
• Evaluated the therapeutic potential of ISR inhibition using ISRIB.

Key Points:

• VAPB P56S expression, unlike WT, reduced neuronal firing and MERC in iPSC-derived MNs.
• VAPB P56S MNs exhibited age-dependent decreases in MMP and heightened sensitivity to ER stress.
• Elevated ATF4 expression and reduced protein synthesis were observed in VAPB P56S MNs, indicative of ISR activation.
• Chemical inhibition of ISR with ISRIB effectively rescued all observed MN disease phenotypes.

Conclusions:

• VAPB P56S mutation contributes to ALS pathogenesis through impaired neuronal function and ER stress.
• The Integrated Stress Response (ISR) pathway plays a critical role in VAPB-linked ALS.
• ISR inhibition represents a promising therapeutic strategy for ALS patients with VAPB mutations.