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.
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Abbreviations
- PD:
-
Parkinson’s disease
- LBs:
-
Lewy bodies
- LNs:
-
Lewy neuritis
- α-syn:
-
Α-synuclein
- TRPC:
-
Transient receptor potential canonical
- Tg:
-
Transgenic
- WT:
-
Wild type
- KO:
-
Knockout
- MMP:
-
Mitochondrial membrane potential
- VDAC:
-
Voltage-dependent anion channel
- ANT:
-
Adenine nucleotide translocator
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Acknowledgements
This work was supported by grants from National Key Research and Development Plan of China (Grant No. 2016YFC1306000); National Natural Science Foundation of China (Grant No. 81371398, 81371200); the Natural Science Foundation of Beijing (Grant No. 7131001); the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges under Beijing Municipality (IDHT20140514).
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Chen, M., Liu, J., Lu, Y. et al. Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice. J Neural Transm 124, 441–453 (2017). https://doi.org/10.1007/s00702-016-1654-y
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DOI: https://doi.org/10.1007/s00702-016-1654-y