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 componen...

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Bibliographic Details
Published in:Neurobiology of disease Vol. 69; pp. 1 - 14
Main Authors: Chu, Yaping, Goldman, Jennifer G., Kelly, Leo, He, Yinzhen, Waliczek, Tracy, Kordower, Jeffrey H.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.09.2014
Elsevier
Subjects:
Aged
Aged, 80 and over
alpha-Synuclein - genetics
alpha-Synuclein - metabolism
Animals
Brain - metabolism
Brain - pathology
Corpus Striatum - metabolism
Corpus Striatum - pathology
Down-Regulation
Female
Humans
Male
Middle Aged
Mitochondria
Mutation
Neurology
Neurons - metabolism
Neurons - pathology
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson's disease
Parkinsonian Disorders - metabolism
Parkinsonian Disorders - pathology
Rats, Sprague-Dawley
Striatum
Substantia nigra
Substantia Nigra - metabolism
Substantia Nigra - pathology
Voltage-Dependent Anion Channel 1 - metabolism
α-Synuclein
α-Synuclein
Striatum
Mitochondria
Parkinson's disease
Substantia nigra
ISSN:0969-9961, 1095-953X, 1095-953X
Online Access:Get full text
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Summary: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. •VDAC1 is decreased in sporadic and experimental Parkinson's disease.•VDAC1 is down-regulated in nigral neurons with α-synuclein inclusions.•VDAC1 was present in fibers with granular but not aggregated α-synuclein.•α-Synuclein overexpression results in reduction of VDAC1.
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ISSN:0969-9961
1095-953X
1095-953X
DOI:10.1016/j.nbd.2014.05.003