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Neuroprotective strategies targeting a-synuclein accumulation and pathology| old_uid | 5348 |
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| title | Neuroprotective strategies targeting a-synuclein accumulation and pathology |
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| start_date | 2008/10/09 |
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| schedule | 11h30 |
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| online | no |
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| location_info | salle de conférence de la PGF |
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| details | Invité par Erwan Bezard |
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| summary | Both clinical and experimental evidence consistently points to ?-synuclein as a key player in the pathogenesis of Parkinson’s disease (PD) and other neurodegenerative disorders (collectively referred to as “synucleinopathies”), justifying the view that this protein represents a promising new target for therapeutic intervention in these diseases. The precise mechanisms by which an endogenously expressed protein like ?-synuclein becomes involved in pathologic processes are still not completely understood. An intriguing clue can be drawn, however, from human genetic studies showing that enhanced ?-synuclein expression due to multiplication mutations of the ?-synuclein gene is associated with familial parkinsonism and dementia. This observation suggests that any condition (besides genomic multiplications) capable of augmenting ?-synuclein levels may contribute to the pathogenesis of PD and other synucleinopathies. Data will be presented showing that toxic agents damaging the nigrostriatal system (this system is particularly vulnerable to the neurodegenerative process of PD) cause an up-regulation of ?-synuclein and modifications of the protein (e.g., nitration and aggregation) similar to those observed in post-mortem PD brains. These data support the hypothesis that toxic insults could contribute to the pathogenesis of synucleinopathies by increasing ?-synuclein level within neurons. We will also discuss two potential strategies against the pathological accumulation of ?-synuclein, one using RNA interference (RNAi) as a means to lower ?-synuclein expression and the other involving lysosomal pathways of protein degradation that, once induced, could facilitate ?-synuclein clearance. RNAi targeting ?-synuclein and drugs acting as inducers of protein degradation could ultimately become valuable strategies for neuroprotective intervention in PD and other human synucleinopathies. |
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| responsibles | Deris |
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