Dr George Tofaris
Wellcome Trust
United Kingdom
Studies on alpha-synuclein degradation and its relevance to Lewy body disease.
Wellcome Trust
994,864
01/04/12
5.0
Parkinson's disease & PD-related disorders
Cognitive impairment | Dementia | Neurodegen | Parkinson
Parkinsons disease (PD), is a common neurodegenerative disorder without pre-symptomatic diagnosis or cure. Although it is established that an accumulation of alpha-synuclein in neurons contributes to PD pathogenesis, the factors influencing the content of this key protein in cells remain poorly understood. I have recently discovered that the ubiquitin-ligase Nedd4 robustly ubiquitinates alpha-synuclein and promotes its degradation by the endosomal-lysosomal pathway. I hypothesize that (a) impair ed degradation of alpha-synuclein by this pathway contributes to the pathogenesis of PD and (b) this pathway can be targeted for neuroprotection. I have the following specific aims: 1. Study in cell models whether Nedd4 regulates the membrane-bound fraction of alpha-synuclein and whether this process involves further post-translational modifications. 2. Investigate using primary neurons whether Nedd4-mediated alpha-synuclein is a target for neuroprotection. 3. Understand how Nedd4 is re gulated in normal and disease states. 4. Study the anatomical distribution, level of expression and post-translational modification of Nedd4 and other endosomal proteins in PD and control brain tissue.