Mouse models of alpha-synucleinopathy and Lewy pathology

Citation
B. Sommer et al., Mouse models of alpha-synucleinopathy and Lewy pathology, EXP GERONT, 35(9-10), 2000, pp. 1389-1403
Citations number
42
Categorie Soggetti
Medical Research General Topics
Journal title
EXPERIMENTAL GERONTOLOGY
ISSN journal
05315565 → ACNP
Volume
35
Issue
9-10
Year of publication
2000
Pages
1389 - 1403
Database
ISI
SICI code
0531-5565(200012)35:9-10<1389:MMOAAL>2.0.ZU;2-B
Abstract
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 .