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Funded Studies

Pathogenetic Mechanisms in Early-onset Parkinsonism Resulting from a Mutation in the Synaptojanin 1 Protein

Study Rationale:                   
Several proteins encoded by Parkinson’s disease (PD) genes have been linked to vesicular traffic (movement of molecules) at synapses (junctions between neurons). These include the protein synuclein, LRRK2 and auxilin. Three recent studies reported a mutation in synaptojanin 1, another protein implicated in synaptic vesicle transport, in early-onset parkinsonism patients. The goal of our study is to investigate mechanisms underlying early-onset parkinsonsism due to synaptojanin 1 mutations.

We hypothesize that the partial impairment of synaptojanin 1 function results in the onset of early-onset Parkinsonism by causing abnormal synaptic vesicles traffic.

Study Design:
We generated models carrying the synaptojanin 1 mutation responsible for early-onset parkinsonism that mimic the clinic symptoms of human patients. Using this model, we will 1) explore the impact of the PD mutation of synaptojanin 1 on the structure and function of neurons by biochemical, physiological and imaging methods, and 2) examine brain pathology induced by the mutation (particularly in the brain regions affected in PD patients). We will also perform genetic analysis to explore the functional relationship of synaptojanin 1 with other PD proteins.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
The methods represent a model to study early onset parkinsonism and more generally disease mechanisms in PD. These investigations, in addition, may reveal novel drug targets to delay the course or even to prevent disease onset in early-onset parkinsonism and potentially also in other forms of Parkinson’s.

Next Steps for Development:
The understanding of mechanisms through which the PD mutation of synaptojanin 1 impact neuronal function may provide insight into other proteins whose regulation may have therapeutic potential. 

Additional Support:
This project was selected for a Stern Discovery Award with support from the former Michael Stern Parkinson's Research Foundation, which merged with The Michael J. Fox Foundation in 2015.


  • Mian Cao, PhD

    New Haven, CT United States

  • Pietro De Camilli, MD

    New Haven, CT United States

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