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Functional Characterization of HIP1R in Parkinson’s Disease

Study Rationale:                   
Intracellular vesicle trafficking is an important mechanism for delivering proteins to their proper location where they can function within cells. Various genes involved in vesicle trafficking have been associated with Parkinson’s disease (PD) including the recently identified huntingtin-interacting protein-1 related (HIP1R) gene. We have identified a rare mutation on HIP1R in a PD patient. Our study aims to (i) identify additional mutations on HIP1R in PD patients; (ii) study genetic interactions between HIP1R, LRRK2 and SNCA; and (iii) to characterize the effects of HIP1R mutations on function.

We hypothesize genetic interaction between HIP1R, LRRK2 and SNCA, and that mutations in HIP1R will affect proper function of intracellular trafficking.

Study Design:
Using advanced sequencing technology, we will screen for additional mutations in different PD cohorts. Identified mutations will be analyzed with several bioinformatic programs for their deleterious effects. Using molecular and cellular techniques, we will characterize the functional effects of these mutations on vesicle trafficking including on endocytosis, a mechanism that permits the entrance of extracellular proteins into the cell, and on actin reorganization, a network of microfilaments that allows for the trafficking of proteins within the cell.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
By investigating the functional significance of new proteins involved in PD, the project will help to piece together the puzzle of protein interactions necessary to cause Parkinson’s disease. Understanding this network of interactions will help to better target therapies.

Next Steps for Development:
If successful, our project will lead to the characterization of HIP1R involvement in PD. It will be important for the future to understand the relationship between HIP1R and others well-characterized proteins involved in PD.

Final Outcome

HIP1R is one of the genes involved in vesicle trafficking, the process of delivering proteins to the location within the cell where they can function. Using advanced technology, we found new rare variants in a recently identified Parkinson’s disease (PD)-associated gene HIP1R. We also described the effect of the R934C mutation -- genetic change -- in the HIP1R gene on actin binding (a step in the process of moving proteins inside the cell) and endocytosis (the process that allows cells to swallow proteins that surround them). This mutation causes reduced actin binding and delayed endocytosis. In addition, our results reveal a direct interaction between the LRKK2 and HIP1R proteins. Two PD-associated variants of the HIP1R gene warrant further characterization to clarify their function. We concluded that HIP1R is involved in Parkinson’s disease through its interaction with LRRK2, the greatest known genetic contributor to PD. To fully understand the involvement of these two proteins in PD, we would need to study how they influence each other’s function.

Presentations & Publications
Pietruszka P, Gan-Or Z, Boudreault-Bouchard M, Rouleau G, Legendre-Guillemin V. A mutation in HIP1R THATCH domain identified in a Parkinson disease affected patient reduced actin binding 


  • Valérie Legendre-Guillemin, PhD

    Chicoutimi PQ Canada

  • Ziv Gan-Or, MD, PhD

    Montreal QC Canada

  • Guy A. Rouleau, MD, PhD, FRCP(C), OQ

    Montreal PQ Canada

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