Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration
Panpan Wang, Xi Chen, Yuanyuan Wang, Congcong Jia, Xinyao Liu, Ying Wang, Haifeng Wu, Huaibin Cai, Han‐Ming Shen, Weidong Le
Abstract
Abstract 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.