Mouse models of α-synucleinopathy and Lewy pathology

The discovery of two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein α-synuclein (αSN) 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 αSN. 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 αSN in the nervous system under control of mouse Thy1 regulatory sequences. These animals develop neuronal α-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 αSN may interfere with a universal mechanism of synapse maintenance. Thy1-transgene expression of wildtype human αSN resulted in comparable pathological changes thus supporting a central role for mutant and wildtype αSN in familial and idiopathic forms of diseases with neuronal α-synucleinopathy and Lewy pathology. The mouse models provide means to address fundamental aspects of α-synucleinopathy and to test therapeutic strategies.