Human Molecular Genetics Advance Access originally published online on February 26, 2009
Human Molecular Genetics 2009 18(10):1779-1794; doi:10.1093/hmg/ddp090
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-Synucleinopathy: neurodegeneration associated with overexpression of the mouse protein
1 School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK 2 Neuroscience, Novartis Institutes for Biomedical Research, Novartis AG CH-4002, Basel, Switzerland
* To whom correspondence should be addressed at: Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK. Tel: +44 2920879068; Fax: +44 2920874116; Email: buchmanvl{at}cardiff.ac.uk
Received January 8, 2009; Revised February 12, 2009; Accepted February 20, 2009
The role of 
-synuclein in pathogenesis of familial and idiopathic forms of Parkinson’s disease, and other human disorders known as -synucleinopathies, is well established. In contrast, the involvement of two other members of the synuclein family, β-synuclein and 
-synuclein, in the development and progression of neurodegeneration is poorly studied. However, there is a growing body of evidence that -synuclein and β-synuclein have opposite neuropathophysiological effects. Unlike -synuclein, overexpressed β-synuclein does not cause pathological changes in the nervous system of transgenic mice and even ameliorates the pathology caused by overexpressed -synuclein. To assess the consequences of excess expression of the third family member, -synuclein, on the nervous system we generated transgenic mice expressing high levels of mouse -synuclein under control of Thy-1 promoter. These animals develop severe age- and transgene dose-dependent neuropathology, motor deficits and die prematurely. Histopathological changes include aggregation of -synuclein, accumulation of various inclusions in neuronal cell bodies and processes, and astrogliosis. These changes are seen throughout the nervous system but are most prominent in the spinal cord where they lead to loss of spinal motor neurons. Our data suggest that down-regulation of small heat shock protein HSPB1 and disintegration of neurofilament network play a role in motor neurons dysfunction and death. These findings demonstrate that -synuclein can be involved in neuropathophysiological changes and the death of susceptible neurons suggesting the necessity of further investigations of the potential role of this synuclein in disease.