Neuropathology and Neurodegeneration in Rodent Brain Induced by Lentiviral Vectormediated Overexpression of α‐Synuclein

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Abstract
Two mutations in α‐synuclein, the main constituent of Lewy bodies, have been identified in familial Parkinson's disease. We have stereotactically injected lentiviral vectors encoding wild‐type and A30P mutant human α‐synuclein in different brain regions (striatum, substantia nigra, amygdala) of mice. Overexpression of α‐synuclein induced timedependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of α‐synuclein in cell bodies and neurites, α‐synuclein‐positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. After one year, α‐synuclein‐ and ubiquitin‐positive neurons displayed a degenerative morphology and a significant loss of α‐synuclein‐positive cells was observed. Similar findings were observed with both the wild‐type and the A30P mutant form of α‐synuclein and this in different brain regions. This indicates that overexpression of α‐synuclein is sufficient to induce Lewy‐like pathology and neurodegeneration and that this effect is not restricted to dopaminergic cells. Our data also demonstrate the use of lentiviral vectors to create animal models for neurodegenerative diseases.