Abnormal alpha-synuclein reduces nigral voltage-dependent anion channel 1 in sporadic and experimental Parkinson's disease.

Both the misfolding of α-synuclein and mitochondrial dysfunction are considered two major contributors to Parkinson's disease (PD). However, the relationship between the two in normal and PD states remains unclear. Here, we report that voltage-dependent anion channel 1 (VDAC1), a major component of the outer mitochondrial membrane known to regulate mitochondrial functions, is down-regulated in response to α-synuclein accumulation and aggregation. Stereological analysis revealed that 58.33% of the neurons were VDAC1 immunoreactive in the remaining neuromelanin laden neurons in the PD group while 87.48% of the nigral neurons were VDAC1 immunoreactive in the age-matched control group. The relative levels of VDAC1 were significantly decreased in PD nigral neurons when compared to age-matched controls. In PD, this decrease was significantly greater in nigral neurons with α-synuclein inclusions. VDAC1 was observed in fibers with granular α-synuclein but not in fibers with aggregated α-synuclein. Viral vector-mediated overexpression of mutant human α-synuclein (A30P) in rats resulted in significantly decreased VDAC1 in nigral neurons and striatal fibers. These results indicate that mitochondrial function associated with VDAC1 is decreased in sporadic and experimental PD, and this decrease is associated with α-synuclein accumulation and aggregation.

Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease.

The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. As terminal field loss seems to precede cell body loss, we tested whether alterations of axonal transport motor proteins would be early features in Parkinson's disease. There was a decline in axonal transport motor proteins in sporadic Parkinson's disease that preceded other well-known nigral cell-related pathology such as phenotypic downregulation of dopamine. Reductions in conventional kinesin levels precede the alterations in dopaminergic phenotypic markers (tyrosine hydroxylase) in the early stages of Parkinson's disease. This reduction was significantly greater in nigral neurons containing α-synuclein inclusions. Unlike conventional kinesin, reductions in the levels of the cytoplasmic dynein light chain Tctex type 3 subunit were only observed at late Parkinson's disease stages. Reductions in levels of conventional kinesin and cytoplasmic dynein subunits were recapitulated in a rat genetic Parkinson's disease model based on over-expression of human mutant α-synuclein (A30P). Together, our data suggest that α-synuclein aggregation is a key feature associated with reductions of axonal transport motor proteins in Parkinson's disease and support the hypothesis that dopaminergic neurodegeneration following a 'dying-back' pattern involving axonal transport disruption.