Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation.
Alpha-synuclein was implicated in Parkinson's disease when missense mutations in the alpha-synuclein gene were found in autosomal dominant Parkinson's disease and alpha-synuclein was shown to be a major constituent of protein aggregates in sporadic Parkinson's disease and other synucleinopathies. We have generated transgenic mice expressing A53T mutant and wild-type human alpha-synuclein. The mutant transgenic protein was distributed abnormally to the axons, perikarya, and dendrites of neurons in many brain areas. In electron microscopic immunogold studies, no aggregation of alpha-synuclein was found in these mice. However, behavior analysis showed a progressive reduction of spontaneous vertical motor activity in both mutant lines correlating with the dosage of overexpression. In addition, deficits of grip strength, rotarod performance, and gait were observed in homozygous PrPmtB mice. Transgenic animals expressing mutant alpha-synuclein may be a valuable model to assess specific aspects of the pathogenesis of synucleinopathies.
Department of Anatomy II (Experimental Neurobiology), University Frankfurt/M, Frankfurt, Germany.
Suzana
S
Gispert
Domenico
D
Del Turco
Lisa
L
Garrett
Amy
A
Chen
David J
DJ
Bernard
John
J
Hamm-Clement
Horst-Werner
HW
Korf
Thomas
T
Deller
Heiko
H
Braak
Georg
G
Auburger
Robert L
RL
Nussbaum
D000818:Animals; D002417:Cattle; D002449:Cell Aggregation / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein