Lipid transfer proteins at ER membrane contact sites sustain lipid homeostasis to suppress C9ORF72-associated ALS pathogenesis

Abstract

Membrane contact sites (MCS) provide unique microenvironments for cellular physiology across intracellular organelles. In particular, lipid transfer proteins (LTPs) operate at the endoplasmic reticulum (ER) MCS to sustain lipid homeostasis. Here, we demonstrate the neuroprotective function of the ER-LTPs in the pathogenesis of C9ORF72-associated amyotrophic lateral sclerosis (C9-ALS). Drosophila genetic screen identified that transgenic ER-LTP depletion selectively enhanced the neurotoxic effects of C9ORF72-derived poly(GR) proteins among other neurodegenerative disease models. Transgenic poly(GR) expression in human cells disrupted ER-plasma membrane MCS and subcellular ER-LTP localization. The pathogenic poly(GR) further impaired lipid homeostasis and lysosomal function via distinct ER-LTPs. Importantly, ALS-relevant mutants of ER-LTPs displayed inappropriate MCS localization and altered lipid homeostasis, as observed in C9-ALS patient neurons. Taken together, our findings uncover a pivotal role for ER MCS-mediated lipid homeostasis in the cellular pathogenesis of C9-ALS.