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Vacuole membrane protein 1 (VMP1), the endoplasmic reticulum (ER)-localized autophagy protein, plays a key role during the autophagy process in mammalian cells. To study the impact of  VMP1 -deficiency on midbrain dopaminergic (mDAergic) neurons, we selectively deleted  VMP1  in the mDAergic neurons of  VMP1  fl/fl / DAT  CreERT2  bigenic mice using a tamoxifen-inducible  CreERT2/loxp  gene targeting system. The  VMP1  fl/fl / DAT  CreERT2  mice developed progressive motor deficits, concomitant with a profound loss of mDAergic neurons in the substantia nigra pars compacta (SNc) and a high presynaptic accumulation of α-synuclein (α-syn) in the enlarged terminals. Mechanistic studies showed that  VMP1  deficiency in the mDAergic neurons led to the increased number of microtubule-associated protein 1 light chain 3-labeled (LC3) puncta and the accumulation of sequestosome 1/p62 aggregates in the SNc neurons, suggesting the impairment of autophagic flux in these neurons. Furthermore,  VMP1  deficiency resulted in multiple cellular abnormalities, including large vacuolar-like structures (LVSs), damaged mitochondria, swollen ER, and the accumulation of ubiquitin +  aggregates. Together, our studies reveal a previously unknown role of VMP1 in modulating neuronal survival and maintaining axonal homeostasis, which suggests that  VMP1  deficiency might contribute to mDAergic neurodegeneration via the autophagy pathway.

Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration