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Convergent activation of the integrated stress response and ER–mitochondria uncoupling in VAPB-associated ALS

Curran Landry,James P Costanzo,M. Mitne-Neto,Mayana Zatz,Ashleigh E. Schaffer,M. Hatzoglou,A. Muotri,H. Miranda

Published 2025 in EMBO Molecular Medicine

ABSTRACT

Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials. The ALS-associated VAPB P56S mutation disrupts ER–mitochondria associated membranes (ER-MAMs) and leads to mitochondrial stress and activation of the integrated stress response (ISR). ISR inhibition restores neuronal function, supporting a precision medicine approach in ALS. The VAPB P56S mutation reduces motor neuron firing, mitochondrial membrane potential, and dampens mRNA translation. ISR activation is heightened in VAPB P56S motor neurons in response to cellular stress. Pharmacological inhibition of the ISR restores mitochondrial function, protein synthesis, and neuronal activity. These findings support ISR inhibition as a genotype-specific therapeutic strategy for ALS. Patient-derived and isogenic iPSC models enable mechanistic insights into ALS8 pathogenesis. The VAPB P56S mutation reduces motor neuron firing, mitochondrial membrane potential, and dampens mRNA translation. ISR activation is heightened in VAPB P56S motor neurons in response to cellular stress. Pharmacological inhibition of the ISR restores mitochondrial function, protein synthesis, and neuronal activity. These findings support ISR inhibition as a genotype-specific therapeutic strategy for ALS. Patient-derived and isogenic iPSC models enable mechanistic insights into ALS8 pathogenesis. The ALS-associated VAPB P56S mutation disrupts ER–mitochondria associated membranes (ER-MAMs) and leads to mitochondrial stress and activation of the integrated stress response (ISR). ISR inhibition restores neuronal function, supporting a precision medicine approach in ALS.

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