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

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 alpha -synuclein (alpha -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.

Automated summary

Deficiency of VMP1 in midbrain dopaminergic neurons leads to neuronal loss and impaired autophagic flux, resulting in various cellular abnormalities that affect neuronal survival and axonal homeostasis.