title: TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease.
abstract: Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery--TOM40--might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Matthias
authors.initials: M
authors.lastname: Elstner
authors.forename: Christoph
authors.initials: C
authors.lastname: Laub
authors.forename: Sarina
authors.initials: S
authors.lastname: Mueller
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Koob
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Emily
authors.initials: E
authors.lastname: Pham
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D005260:Female; D015870:Gene Expression; D054629:Genome, Mitochondrial; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009154:Mutation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D051844:alpha-Synuclein; C455940:mitochondrial outer membrane protein 35-kDa, mouse