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Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis.

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    Vesicle-associated membrane protein-associated protein-B (VAPB) P56S mutation impairs motor neuron function by disrupting mitochondrial-ER contact and increasing ER stress. Inhibition of the Integrated Stress Response (ISR) rescued these disease phenotypes, suggesting a therapeutic target for ALS.

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    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.