eprintid: 1521082 rev_number: 28 eprint_status: archive userid: 608 dir: disk0/01/52/10/82 datestamp: 2016-10-17 10:22:49 lastmod: 2021-09-19 23:53:00 status_changed: 2016-10-17 10:22:49 type: article metadata_visibility: show creators_name: Ludtmann, M creators_name: Angelova, P creators_name: Ninkina, N creators_name: Gandhi, S creators_name: Buchman, V creators_name: Abramov, A title: Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 note: Copyright © 2016 Ludtmann et al. This article is freely available online through the J Neurosci Author Open Choice option. 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. SIGNIFICANCE STATEMENT: Misfolded α-synuclein aggregations in the form of Lewy bodies have been shown to be a pathological hallmark in histological staining of Parkinson's disease (PD) patient brains. It is known that misfolded α-synuclein is a key driver in PD pathogenesis, but the physiological role of unfolded monomeric α-synuclein remains unclear. Using neuronal cocultures and isolated brain mitochondria of α-, β-, and γ-synuclein knock-out mice and monomeric α-synuclein, this current study shows that α-synuclein in its unfolded monomeric form improves ATP synthase efficiency and mitochondrial function. The ability of monomeric α-synuclein to enhance ATP synthase efficiency under physiological conditions may be of importance when α-synuclein undergoes the misfolding and aggregation reported in PD. date: 2016-10-12 date_type: published publisher: Society for Neuroscience official_url: http://doi.org/10.1523/JNEUROSCI.1659-16.2016 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1183055 doi: 10.1523/JNEUROSCI.1659-16.2016 lyricists_name: Abramov, Andrey lyricists_name: Gandhi, Sonia lyricists_name: Ludtmann, Marthe lyricists_name: Stroh, Plamena lyricists_id: AABRA58 lyricists_id: SGAND43 lyricists_id: MLUDT01 lyricists_id: PSTRO69 actors_name: Ludtmann, Marthe actors_id: MLUDT01 actors_role: owner full_text_status: public publication: The Journal of Neuroscience volume: 36 number: 41 pagerange: 10510-10521 issn: 1529-2401 citation: Ludtmann, M; Angelova, P; Ninkina, N; Gandhi, S; Buchman, V; Abramov, A; (2016) Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase. The Journal of Neuroscience , 36 (41) pp. 10510-10521. 10.1523/JNEUROSCI.1659-16.2016 <https://doi.org/10.1523/JNEUROSCI.1659-16.2016>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1521082/1/10510.full.pdf