Neuropathology in mice expressing human α-synuclein

Abstract

The presynaptic protein α-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. α-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the α-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human α-synuclein in the nervous system of transgenic mice generated animals with neuronal α-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuro-muscular junctions in several muscles examined, suggesting that α-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human α-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type α-synuclein in familial and idiotypic forms of diseases with neuronal α-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of α-synucleinopathy and test therapeutic strategies.