Elsevier

Neuroscience Letters

Volume 486, Issue 3, 17 December 2010, Pages 235-239
Neuroscience Letters

Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo

https://doi.org/10.1016/j.neulet.2010.09.061Get rights and content

Abstract

Alpha-synuclein is the major protein component of Lewy bodies, a cardinal pathological feature of the degenerating Parkinsonian brain. Alpha-synuclein has been reported to be able to intercalate into membranes via formation of an alpha-helical structure at its N-terminal end. Recent in vitro studies from various laboratories have demonstrated that alpha-synuclein can physically associate with mitochondria and interfere with mitochondrial function. α-Syn predominantly associates with the inner mitochondrial membrane, where it can apparently interact with complex I resulting in reduced mitochondrial complex I activity and increased free radical production. However, the effect of in vivo alpha-synuclein accumulation within dopaminergic neurons on mitochondrial function has not been thoroughly studied. Examination of transgenic animals which overexpress the familial mutant A53T form of the protein selectively within dopaminergic neurons reveals that A53T localizes to the mitochondrial membranes as monomers and oligomers particularly under conditions of proteasomal inhibitory stress, and that this localization coincides with a selective age-related mitochondrial complex I inhibition and decreased substrate-specific respiration along with increases in mitochondrial autophagy (mitophagy).

Research highlights

▶ α-Syn physically localizes to dopaminergic mitochondria in vivo and impacts on mitochondrial function. ▶ Localization coincides with a selective age-related mitochondrial complex I inhibition and decreased substrate-specific respiration. ▶ Also observed an increase in lysosome-mediated mitochondrial autophagy (mitophagy) in A53T overexpressing midbrain dopaminergic neurons, likely a compensatory attempt to remove defective mitochondria.

Section snippets

Conflict of interest

The authors report no conflicts of interest.

Acknowledgements

We would like to thank Daniel Crippen for technical assistance with EM studies and Dr. Bharat Srinivas for early discussions on this project. This work was financially supported by NIH R01 AG12141 to JKA and American Parkinson's Disease Association to SJC.

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