title: Voltage-dependent anion channel involved in the α-synuclein-induced dopaminergic neuron toxicity in rats.
abstract: Inclusion bodies containing the neural protein α-synuclein (α-syn) are observed in several neurodegenerative diseases, including Parkinson's disease (PD). Furthermore, over-expression of α-syn in rat brain partly mimics the neuropathological and behavioral features of PD by triggering the degeneration of dopaminergic neurons in the substantia nigra (SN). Mitochondrial dysfunction is also central to PD pathogenesis, and α-syn is found in the mitochondria. However, the precise mechanisms of α-syn-induced neurotoxicity remain elusive. To examine the potential mechanisms of α-syn-induced neurodegeneration, we over-expressed α-syn in the SN of rats using a recombinant adeno-associated viral vector (rAAV-syn). Immunohistochemical and immunogold labeling results indicated that α-syn was successfully over-expressed in the SN and striatum after vector injection. The number of tyrosine hydroxylase-positive (dopaminergic) neurons was significantly reduced in rats injected with rAAV-syn when compared with control rats. Compared with control rats, the density of α-syn-conjugated gold particles was greater in the axons, cytoplasm, nuclei, and notably also in the mitochondria of SN neurons in rAAV-syn-injected rats. In addition, SN neurons transfected with rAAV-syn exhibited swollen mitochondria with discontinuous outer membranes and internal vacuole-like structures, strongly suggesting α-syn-induced mitochondrial dysfunction. Mitochondria in rAAV-syn-injected rats were also observed in autophagosomes. α-Syn co-immunoprecipitated with voltage-dependent anion channel 1 (VDAC1), a component of the mitochondrial permeability transition pore (mPTP) that induces mitochondrial uncoupling and apoptosis. Over-expression of α-syn may cause the degeneration of dopaminergic neurons through an interaction with mitochondrial VDAC1, which leads to mPTP activation, mitochondrial uncoupling, and cell death.
authors.affiliation: Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education,  Beijing Institute of Brain Disorders,  Capital Medical University, Beijing 100069,  China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Lu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Cai
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Chunli
authors.initials: C
authors.lastname: Duan
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C494764:Vdac1 protein, rat; D051844:alpha-Synuclein; D050995:Voltage-Dependent Anion Channel 1; D004298:Dopamine