Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation.

Proteotoxicity induced by misfolded or aggregated proteins causes progressive neuronal damage. The endoplasmic reticulum (ER) protein quality control (ERQC) pathways are responsible for mitigating the accumulation of these misfolded or aggregated proteins, thus reducing proteotoxicity. Enhancing ERQC pathways is a promising strategy for treating neurodegenerative diseases. However, the mechanisms governing the initiation and degradation of misfolded or aggregated proteins in neurons remain largely unknown in vivo. In studying the maturation of proAVP in mouse AVP neurons, this study discovers that autophagy and ER-associated degradation (ERAD) ERQC pathways collaborate to maintain proAVP maturation and protect AVP neuron survival against proteotoxicity. Autophagy deficiency in mouse AVP neurons leads to the late-onset of diabetes insipidus. Mechanistically, autophagy selectively degrades mutant proAVP aggregates and endogenous HRD1 of the SEL1L-HRD1 ERAD complex through FAM134B mediated ER-phagy. HRD1 induction is responsible for reducing proAVP aggregation and maintaining AVP neuron function and survival under autophagy deficiency. Thus, autophagy and ERAD form a dual-protection system that orchestrates prohormone maturation and endocrine neuron survival, providing new insights in the complexity of neuroendocrinology and the intrinsic mechanism of neurodegenerative diseases, with therapeutic potential in protein folding diseases.