TY - JOUR
T1 - Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration
AU - Wang, Panpan
AU - Chen, Xi
AU - Wang, Yuanyuan
AU - Jia, Congcong
AU - Liu, Xinyao
AU - Wang, Ying
AU - Wu, Haifeng
AU - Cai, Huaibin
AU - Shen, Han Ming
AU - Le, Weidong
N1 - Funding Information:
This work was supported by funding from the National Nature Science Foundation of China (NSFC 81771521), the National Key Research and Development Program of China (2016YFC1306600), and Key Realm R & D Program of Guangdong Province (2018B030337001). In addition, this manuscript was also contributed in part by the Intramural Research Program of National Institute on Aging, National Institutes of Health (Z01-AG000944, AG000928).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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 VMP1fl/fl/DATCreERT2 bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1fl/fl/DATCreERT2 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.
AB - 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 VMP1fl/fl/DATCreERT2 bigenic mice using a tamoxifen-inducible CreERT2/loxp gene targeting system. The VMP1fl/fl/DATCreERT2 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.
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U2 - 10.1038/s41419-021-03412-5
DO - 10.1038/s41419-021-03412-5
M3 - Article
C2 - 33483473
AN - SCOPUS:85099970182
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 1
M1 - 116
ER -