Impaired organelle turnover in the FAM134B-mediated neuropathy

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Hereditary sensory and autonomic neuropathies (HSAN) are neurodegenerative disorders characterized by severe sensory loss and autonomic dysfunction. Affected individuals suffer from ulcerations and injuries because they lack an acute pain response which alerts the body of potential tissue damage. We demonstrated that loss-of-function mutations in the previously uncharacterized FAM134B gene lead to a severe form of HSAN in humans. Subsequently, we identified FAM134B as the first ER-specific autophagy receptor which facilitates endoplasmic reticulum (ER) degradation by selective autophagy (ER-phagy). This effect is mediated by the specific interaction of FAM134B with LC3 and GABARAPL2, small ubiquitin-like autophagy modifiers that are critical for both targeting and engulfing cargoes for subsequent lysosomal degradation. Consistently, disruption of Fam134b in mice results in expansions of the ER, inhibition of ER turnover, and degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover. This extension proposal will address the timing and localization of FAM134B-mediated organelle turnover and the downstream effects of altered ER-phagy. We will also investigate the phenotypic consequences of the disruption of the homologous Fam134a and Fam134c genes in mice as well the role of these genes in organelle turnover.