Monomeric alpha-synuclein exerts a physiological role in brain ATP synthase

Ludtmann, M H R; Angelova, P R; Ninkina, N; Gandhi, S; Buchman, V L; Abramov, A Y

Abstract

Misfolded α-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded α-synuclein is limited. Using brains of mice lacking α-, β-, and γ-synuclein, we report that extracellular monomeric α-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit α, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of α-, β-, and γ-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded α-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that α-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity.

Citation

Ludtmann, M. H. R., Angelova, P. R., Ninkina, N., Gandhi, S., Buchman, V. L., & Abramov, A. Y. (2016). Monomeric alpha-synuclein exerts a physiological role in brain ATP synthase. Journal of Neuroscience, 36(41), 10510-10521. https://doi.org/10.1523/JNEUROSCI.1659-16.2016

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2016
• Publication Date: Oct 12, 2016
• Deposit Date: Jun 30, 2018
• Publicly Available Date: Aug 23, 2018
• Journal: JOURNAL OF NEUROSCIENCE
• Print ISSN: 0270-6474
• Publisher: Society for Neuroscience
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Issue: 41
• Pages: 10510-10521
• DOI: https://doi.org/10.1523/JNEUROSCI.1659-16.2016
• Public URL: https://rvc-repository.worktribe.com/output/1395226