Chemical changes in the protein alpha-synuclein, such as the binding of phosphate groups (phosphorylation), are characteristic of Parkinson's disease and related alpha-synucleinopathies. However, whether this modification actually promotes or inhibits alpha-synuclein aggregation and neurotoxicity associated with PD remains unclear. This understanding is critical for elucidating the role of alpha-synuclein in PD and for development of therapeutic strategies. The research team plans to apply an integrative approach using animal modeling, molecular/cellular biology and biophysical approaches representing the first attempt to address this subject in a comprehensive manner.
To determine the relationship between phosphorylation of the alpha-synuclein protein and neurodegeneration, we plan to evaluate the biochemical and functional consequences of delivering various modified forms of alpha-synuclein directly to the rodent brain. We will deliver either various forms of the protein that mimic its phosphorylation, or we will deliver the unmodified a-synuclein protein along with enzymes believed to selectively phosphorylate it. These studies will be carried out using pre-clinical models based on adeno-associated viral vector-mediated alpha-synuclein delivery to the substantia nigra developed by the Aebischer group. This genetic model shows strong correlation between alpha-synuclein overexpression, formation of a-synuclein aggregates and degeneration of nigral neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Increasing evidence suggests that chemical modifications such as phosphorylation may be an important regulator of alpha-synuclein aggregation, Lewy body formation and death of neurons. If it turns out that phosphorylation constitutes a primary trigger for alpha-synuclein-induced toxicity, the identification of the enzymes involved in modulating alpha-synuclein aggregation and toxicity could present viable targets for therapeutic strategies for PD. This approach is likely to capture the interest of the pharmaceutical industry owing to the wealth of knowledge and expertise on the development of kinase inhibitors.
A detailed molecular understanding of the functional consequences of phosphorylation could reveal new insight into the normal biology of alpha-synuclein and the mechanisms by which it contributes to neurodegeneration in PD and related disorders. More specifically, the proposed studies will allow us to answer the following questions: Can we block alpha-synuclein aggregation and/or toxicity in the brain through modulation of its phosphorylation state(s)?