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

Authors


  • From the Gene Therapy Program, Katholieke Universiteit Leuven, Leuven, Belgium.

Corresponding author: V. Baekelandt, Kapucunenvoer 33 VCTB+5, B-3000 Leuven, Belgium (e-mail: veerle.baekelandt@med.kuleuven.ac.be)

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.

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