Objective/Rationale:
Research data have recently indicated that pathology in Parkinson’s disease (PD) starts at the synapse, the part of the neurons where release of dopamine occurs, dysfunction of which leads to neuronal death via a “dying back” process. We aim to determine whether increased levels of cysteine string protein alpha (CSPalpha), a chaperon protein involved in the assembly of a protein complex called SNARE, involved in release of neurotransmitters like dopamine, will be able to rescue the abnormal dopamine release observed in the striatum of the human 1-120 truncated alpha-synuclein transgenic pre-clinicalpre-clinical line that represents a model of the early stages of PD.
Project Description:
Alpha-synuclein, the main protein that forms Lewy bodies, the characteristic protein aggregates present in patients with PD. is accumulated at the site of connection between nerve cells, or synapse, in the striatum of our a-Syn 1-120 transgenic pre-clinicalpre-clinical model, which represents early stages of PD pathology. This accumulation is associated with re-distribution of components of the SNARE complex (proteins, that are crucial in maintaining neurotransmitter release machinery), and progressive, age-dependent reduction of dopamine release from striatum. Chaperon proteins (e.g. CSPalpha) regulate assembly of SNARE complex, and alpha-synuclein rescues neurodegeneration due to lack of CSPalpha. We will examine whether virus-mediated over-expression of CSPalpha will restore the deficit in exocytosis in vitro in alpha-synuclein expressing cell lines and in vivo in the human 1-120 truncated alpha-synuclein transgenic pre-clinical line. In particular, we will overexpress CSPalpha in cells overexpressing alpha-synuclein and showing a deficit in exocytosis. Furthermore, we will produce viruses expressing the CSPalpha protein that will be injected in the brain of transgenic models expressing human 1-120 alpha-synuclein to determine whether CSPalpha can also rescue exocytosis in vivo in the pre-clinical brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Alpha-synuclein is a crucial protein involved in the development of PD - however its function is not completely understood. A mounting body of evidence indicates participation of alpha-synuclein in maintaining of normal cell-to-cell communication by ensuring proper functioning of synapse, where it participates in vesicle docking and neurotransmitter release. Our project will help to clarify whether CSPalpha overexpression could help to restore a normal release of neurotransmitter in a synapse damaged by alpha-synuclein accumulation providing further insights into early stages of PD and its possible treatmnent.
Anticipated Outcome:
This study will reveal the relevance of alpha-synuclein aggregation at the synapse as a target for PD treatment. If preventing/correcting SNARE redistribution will restore a normal dopamine release it will indicate a novel direction for therapeutic intervention for PD.