Human Gene Therapy · 2002 · 210 citations · 31 references
Life SciencesNeurobiologyNeuroscienceMolecular NeurobiologyMolecular NeuroscienceNeurodegenerationMolecular Basis Of NeurodegenerationNeurodegeneration MechanismsNeurodegenerative DiseasesNeurodegenerative DisordersParkinson DiseaseParkinsonian DisordersAdeno-associated Viral TransgenesisDopaminergic NeurodegenerationNeurologic DeficitsNigrostriatal Dopamine SystemParkinson Disease PathologyParkinsonian DegenerationSynucleinopathy ModelsTransgene Expression
Somatic cell gene transfer was used to express a mutant form of alpha-synuclein (alpha-syn) that is associated with Parkinson's disease (PD) in the rat substantia nigra (SN), a brain region that, in humans, degenerates during PD. DNA encoding the A30P mutant of human alpha-syn linked to familial PD was incorporated into an adeno-associated virus vector, which was injected into the adult rat midbrain. The cytomegalovirus/chicken beta-actin promoter was used to drive transgene expression. Over a 1-year time course, this treatment produced three significant features relevant to PD: (1) accumulation of alpha-syn in SN neuron perikarya, (2) Lewy-like dystrophic neurites in the SN and the striatum, and (3) a 53% loss of SN dopamine neurons. However, motor dysfunction was not found in either rotational or rotating rod testing. The lack of behavioral deficits, despite the significant cell loss, may reflect pathogenesis similar to that of PD, where greater than 50% losses occur before motor behavior is affected.
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Mihael H. Polymeropoulos, Christian Lavedan, Elisabeth Leroy et al. · Science · 1997 · 8.2K citations
A Drosophila model of Parkinson's disease
Mel Β. Feany, Welcome Bender · Nature · 2000 · 2.1K citations