Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein.
Two mutations in alpha-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 alpha-synuclein in different brain regions (striatum, substantia nigra, amygdala) of mice. Overexpression of alpha-synuclein induced time-dependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of alpha-synuclein in cell bodies and neurites, alpha-synuclein-positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. After one year, alpha-synuclein- and ubiquitin-positive neurons displayed a degenerative morphology and a significant loss of alpha-synuclein-positive cells was observed. Similar findings were observed with both the wild-type and the A30P mutant form of alpha-synuclein and this in different brain regions. This indicates that overexpression of alpha-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.
Lauwers
Erwin
E
Gene Therapy Program, Katholieke Universiteit Leuven, Leuven, Belgium.
Debyser
Zeger
Z
Van Dorpe
Jo
J
De Strooper
Bart
B
Nuttin
Bart
B
Baekelandt
Veerle
V
D000679:Amygdala / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007181:Inclusion Bodies, Viral / Q000378:metabolism / Q000473:pathology; D016180:Lentivirus Infections / Q000378:metabolism*; D020961:Lewy Body Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000295:instrumentation / Q000379:methods; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000821:virology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051843:Synucleins; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase