Neuropathology in mice expressing human alpha-synuclein

The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are gene tically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human alpha- synuclein in the nervous system of transgenic mice generated animals with n euronal alpha-synucleinopathy, features strikingly similar to those observe d in human brains with Lewy pathology, neuronal degeneration, and motor def ects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons app eared particularly vulnerable. Motor neuron pathology included axonal damag e and denervation of neuromuscular junctions in several muscles examined, s uggesting that alpha-synuclein interfered with a universal mechanism of syn apse maintenance. Thy1 transgene expression of wild-type human alpha-synucl ein resulted in similar pathological changes, thus supporting a central rol e for mutant and wild-type alpha-synuclein in familial and idiotypic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. These m ouse models provide a means to address fundamental aspects of alpha-synucle inopathy and test therapeutic strategies.