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Mechanism of alpha-synuclein toxicity in Parkinson's disease.

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  • UserProfessor Maria Grazia Spillantini, Department of Clinical Neurosciences, Cambridge
  • ClockTuesday 29 September 2009, 11:00-11:30
  • HouseWest Road Concert Hall.

If you have a question about this talk, please contact Hannah Critchlow.

This talk is part of the Cambridge Clinical Neuroscience and Mental Health Symposium, 29th – 30th September 2009 at West Road Concert Hall. This event is free to attend for cambridge neuroscientists although registration is required. To register, and for further information, please visit: http://www.neuroscience.cam.ac.uk/cnmhs/

Abstract: Parkinson’s disease (PD) is the most common movement disorder clinically characterized by rigidity, resting tremor and bradikenisia which are associated with degeneration of neurones in the substantia nigra. Neuropathologically PD is characterized by the presence of intracellular filamentous protein aggregates known as Lewy bodies. Genetic mutations and multiplications of the alpha-synuclein gene cause familial forms of PD and alpha-synuclein has been shown to be the major component of the Lewy bodies (1). These findings clearly associate the pre-synaptic protein alpha-synuclein to PD pathogenesis although, its toxic function remain unclear as unclear is whether proteasome dysfunction and oxidative stress are a cause or consequence of alpha-synuclein accumulation. We have produced a transgenic mouse that expresses truncated 1-120 human alpha-synuclein under the control of the tyrosine hydroxylase promoter. In these mice truncated alpha-synuclein aggregates into granular and filamentous material and this aggregation is associated with dopamine loss and appearance of motor impairment in the absence of dopaminergic cell death (2). In these mice we do not find alterations in proteasome and aconitase activities or authophagy while an altered synaptic distribution of alpha-synuclein is present. This result suggests that PD could start at the synapse.

References: 1- Tofaris GK, Spillantini MG. Physiological and pathological properties of alpha-synuclein. Cell Mol Life Sci. 64, 2194-201, 2007

2-Tofaris GK, Garcia Reitböck P., O’Connell M., Ghetti B., Humby T., Lambourne L., Gossage H., Emson P.C., Wilkinson L.S., Goedert M., Spillantini M.G.: Pathological changes in dopaminergic neurones in mice transgenic for human -synuclein (1-120): implications for Lewy body disorders. J Neurosci 26, 3942-3950, 2006.

Biosketch: Maria Grazia Spillantini is Professor of Molecular Neurology at the Clinical School of the University of Cambridge, UK. She was born in Arezzo, Italy. After receiving a Laurea in Biological Sciences, summa cum Laude, in 1981 from the University of Florence, Italy, she pursued research at the Department of Clinical Pharmacology of the University of Florence, at the Unit’s de Neurobiologie of the INSERM in Paris and at the Molecular Neurobiology Unit of the Medical Research Council in Cambridge. In 1987 she moved to the Medical Research Council Laboratory of Molecular Biology, where first, working in Dr Michel Goedert’s group, she obtained a Ph.D. in Molecular Biology from Cambridge University (Peterhouse) and later she worked as postdoctoral fellow with Prof. Sir Aaron Klug. In 1996 she moved to the Brain Repair Centre of the University of Cambridge at the Department of Clinical Neurosciences where she is at present. Her group works on the molecular neuropathology of diseases characterised by tau and alpha-synuclein aggregates. She identified alpha-synuclein as the major component of the Lewy bodies in Parkinson’s disease and dementia with Lewy bodies and described one of the first mutations in the Tau gene leading to Frontotemporal dementia and Parkinsonism linked to chromosome 17. She is an official fellow of Clare Hall and life member of Peterhouse

This talk is part of the Clinical Neuroscience and Mental Health Symposium series.

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