TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

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.