Apoptosis-inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins
Ann Neurol.. 2010-04-06; : n/a-n/a
DOI: 10.1002/ana.22034
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OBJECTIVE: Mitochondrial complex I deficits have long been associated with
Parkinson disease (PD). However, it remains unknown whether such defects
represent a primary event in dopaminergic neurodegeneration.
METHODS: Apoptosis-inducing factor (AIF) is a mitochondrial protein that,
independently of its proapoptotic properties, plays an essential physiologic role
in maintaining a fully functional complex I. We used AIF-deficient harlequin (Hq)
mice, which exhibit structural deficits in assembled complex I, to determine
whether primary complex I defects linked to AIF depletion may cause dopaminergic
neurodegeneration.
RESULTS: Despite marked reductions in mitochondrial complex I protein levels, Hq
mice did not display apparent alterations in the dopaminergic nigrostriatal
system. However, these animals were much more susceptible to exogenous
parkinsonian complex I inhibitors, such as
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Subtoxic doses of MPTP,
unable to cause damage to wild-type animals, produced marked nigrostriatal
dopaminergic degeneration in Hq mice. This effect was associated with exacerbated
complex I inhibition and increased production of mitochondrial-derived reactive
oxygen species (ROS) in Hq brain mitochondria. The antioxidant superoxide
dismutase-mimetic compound tempol was able to reverse the increased
susceptibility of Hq mice to MPTP. Supporting an instrumental role for
mitochondrial-derived ROS in PD-related neurodegeneration, transgenic mice
overexpressing mitochondrially targeted catalase exhibited an attenuation of
MPTP-induced mitochondrial ROS and dopaminergic cell death.
INTERPRETATION: Structural complex I alterations linked to AIF deficiency do not
cause dopaminergic neurodegeneration but increase the susceptibility of
dopaminergic neurons to exogenous parkinsonian neurotoxins, reinforcing the
concept that genetic and environmental factors may interact in a common molecular
pathway to trigger PD.
DOI: 10.1002/ana.22034
PMID: 20695011 [Indexed for MEDLINE]