title: Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice.
abstract: Aberrant α-synuclein (α-syn) accumulation has been shown to impair mitochondrial function by reducing mitochondrial membrane potential (MMP). However, the underlying mechanisms remain elusive. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca2+channels, among which TRPC3 is the only one that is localized in mitochondria and plays a role in maintaining the normal MMP. This raises a possibility that altered TRPC3 expression may play a role in the mitochondrial dysfunction induced by α-syn accumulation. To demonstrate this possibility, we first examined the expressions of mitochondrial TRPC3 in the brains of aging monkeys and α-syn transgenic and wild-type mice. We showed that α-syn levels increased in mitochondria in an age-dependent manner that was positively correlated to an elevation of mitochondrial TRPC3. This correlation was more prominent in the striatum than in the cerebellum, possibly due to the greater age-dependent α-syn accumulation in the striatum than in the cerebellum. We then used primary neurons overexpressing α-syn to investigate the effect of the α-syn-induced elevation of mitochondrial TRPC3 on the MMP and apoptotic cell death. We found that neurons with overexpressed α-syn had increased mitochondrial TRPC3 and decreased MMP, which were accompanied by increased number of apoptotic neurons. Suppressing TRPC3 expression partially reversed the reduction of MMP and alleviated the apoptotic cell death, indicating that the mitochondrial TRPC3 may play a role in the mitochondrial dysfunction in neurons with α-syn accumulation that may occur in not only the aged brain but also the brain with PD.
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Duan
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, China.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China.
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, China. yushun103@163.com.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China. yushun103@163.com.
authors.forename: Shun
authors.initials: S
authors.lastname: Yu
authors.affiliation: Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, 10 Xi Tou Tiao, You Anmen, Beijing, 100069, China. huiyang@ccmu.edu.cn.|Center for Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Beijing, China. huiyang@ccmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D051844:alpha-Synuclein
keywords: Brain; Mitochondria; Parkinson’s disease; TRPC3; α-Synuclein