α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.

Nat Commun 2018 06 12;9(1):2293. Epub 2018 Jun 12.

Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04422-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997668PMC
June 2018
19 Reads
10.740 Impact Factor

Publication Analysis

Top Keywords

atp synthase
20
permeability transition
8
transition pore
8
ptp opening
8
interact atp
8
parkinson's disease
8
α-synuclein
6
synthase
5
atp
5
pore ptp
4
including atp
4
probability permeability
4
events increase
4
oxidation events
4
increase probability
4
triggering mitochondrial
4
cell death
4
death notably
4
notably inhibition
4
ultimately cell
4

References

(Supplied by CrossRef)

R Kruger et al.
Nat. Genet. 1998

MH Polymeropoulos et al.
Science 1997

MC Chartier-Harlin et al.
Lancet 2004

AB Singleton et al.
Science 2003

DE Mor et al.
Nat. Neurosci. 2017

BI Giasson et al.
J. Biol. Chem. 2001

N Cremades et al.
Cell 2012

E Deas et al.
Antioxid. Redox Signal. 2016

PR Angelova et al.
J. Cell Sci. 2016

MH Ludtmann et al.
J. Neurosci. 2016

MH Horrocks et al.
ACS Chem. Neurosci. 2016

Similar Publications