Journal
CELL DEATH & DISEASE
Volume 12, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03412-5
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Funding
- National Nature Science Foundation of China [NSFC 81771521]
- National Key Research and Development Program of China [2016YFC1306600]
- Key Realm R & D Program of Guangdong Province [2018B030337001]
- Intramural Research Program of National Institute on Aging, National Institutes of Health [Z01-AG000944, AG000928]
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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.
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.
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