Mouse models of alpha-synucleinopathy and Lewy pathology.
The discovery of two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein alpha-synuclein (alphaSN) that are genetically linked to rare familial forms of Parkinson's disease and its accumulation in Lewy bodies and Lewy neurites has triggered several attempts to generate transgenic mice overexpressing human alphaSN. Analogous to a successful strategy for the production of transgenic animal models for Alzheimer's disease we generated mice expressing wildtype and the A53T mutant of human alphaSN in the nervous system under control of mouse Thy1 regulatory sequences. These animals develop neuronal alpha-synucleinopathy, striking features of Lewy pathology, neuronal degeneration and motor defects. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions, suggesting that alphaSN may interfere with a universal mechanism of synapse maintenance. Thy1-transgene expression of wildtype human alphaSN resulted in comparable pathological changes thus supporting a central role for mutant and wildtype alphaSN in familial and idiopathic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. The mouse models provide means to address fundamental aspects of alpha-synucleinopathy and to test therapeutic strategies.
Sommer
B
B
Nervous System Research, Novartis Pharma Inc., CH 4002, Basel, Switzerland. bernd.sommer@pharma.novartis.com
Barbieri
S
S
Hofele
K
K
Wiederhold
K
K
Probst
A
A
Mistl
C
C
Danner
S
S
Kauffmann
S
S
Spooren
W
W
Tolnay
M
M
Bilbe
G
G
van der Putten H
Kafmann
S
S
Caromi
P
P
Ruegg
M A
MA
D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051843:Synucleins; D019076:Transgenes / Q000235:genetics; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein