The discovery of two missense mutations (A53T and A30P) in the gene encodin
g the presynaptic protein alpha -synuclein (alpha SN) that are genetically
linked to rare familial forms of Parkinson's disease and its accumulation i
n Lewy bodies and Lewy neurites has triggered several attempts to generate
transgenic mice overexpressing human alpha SN. Analogous to a successful st
rategy for the production of transgenic animal models for Alzheimer's disea
se we generated mice expressing wildtype and the A53T mutant of human alpha
SN in the nervous system under control of mouse Thy1 regulatory sequences.
These animals develop neuronal alpha -synucleinopathy, striking features o
f Lewy pathology, neuronal degeneration and motor defects. Neurons in brain
stem and motor neurons appeared particularly vulnerable. Motor neuron patho
logy included axonal damage and denervation of neuromuscular junctions, sug
gesting that alpha SN may interfere with a universal mechanism of synapse m
aintenance. Thy1-transgene expression of wild-type human alpha SN resulted
in comparable pathological changes thus supporting a central role for mutan
t and wildtype alpha SN in familial and idiopathic forms of diseases with n
euronal alpha -synucleinopathy and Lewy pathology. The mouse models provide
means to address fundamental aspects of alpha -synucleinopathy and to test
therapeutic strategies. (C) 2000 Elsevier Science Inc. All nights reserved
.