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