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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\u2010associated 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\u2010onset of diabetes insipidus. Mechanistically, autophagy selectively degrades mutant proAVP aggregates and endogenous HRD1 of the SEL1L\u2010HRD1 ERAD complex through FAM134B mediated ER\u2010phagy. 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