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Characterization of PARK16

Recently, a novel region of the genome containing genetic information predisposing to the development of Parkinson’s disease has been discovered through a collaborative study of European and Asian researchers. This region, namely PARK16, contains several genes and will be investigated to identify the exact gene and genetic alteration which increases the risk of disease. The primary focus will be on RAB7L1 since a novel gene, known to interact with RAB7 proteins, has been found to carry mutations causing Parkinson’s disease.

Project Description:
We have recently confirmed the presence of genetic causes of Parkinson’s disease in PARK16, but exclusively in the Asian population. Therefore to identify the cause of disease we will analyze the DNA sequence for those genes in PARK16 in Parkinson’s disease patients of Chinese ethnicity from Taiwan. Initial studies will be performed in collaboration with Dr. Ruey-Mei Wu, Chair of Neurology at the National Hospital in Taipei. Any interesting variant potentially causing disease will be further analyzed in Parkinson’s disease patients from North America, Europe and North Africa. As well as the sequence of DNA we will evaluate the effect of any mutation identified in protein production, protein function, vesicular trafficking and cell survival.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will lead to a better understanding of genetic factors that predispose to Parkinson’s disease. The knowledge gained can be applied to the development of cellular and animal models, with which to study the molecular mechanisms that lead to disease in patients. The models will also provide the foundation to develop novel therapeutics. The insights gained and resources developed will improve diagnosis, nominate novel drug targets and the models to test them, and may lead to a preventive treatment and potentially a cure.

Anticipated Outcome:
This work is expected to identify a novel gene which contains mutation/s leading to an increased likelihood of developing Parkinson’s disease. Once this gene and its mutation/s have been identified, we will evaluate the mechanism by which these genetic alterations lead to disease. This knowledge will aid the global community of researchers to better understand how Parkinson’s disease develops, therefore accelerating the progress of research and push us closer to find a cure for Parkinson’s disease.

Final Outcome

Before the characterization of all genes located in the PARK16 region, replication of the initial findings was necessary to confirm the presence of genetic variants leading to an increased risk of developing Parkinson disease. To this end, we evaluated a multi-ethnic group consisting of over 5,000 patients and healthy individuals. This study confirmed that genetic risk factors were present, but exclusively found in the Asian population. To identify what specific variants cause the increased likelihood of developing Parkinson disease, we looked for genetic variants in patients with a family history of disease. This analysis identified several novel variants; however none of them appeared to be the cause of disease in those patients. Since genetic changes did not account for the increase susceptibility to disease, we evaluated gene expression as a potential culprit for disease risk. We examined the expression of all the genes located in PARK16, and evaluated whether a correlation between variants associated with disease risk and gene expression was present. In addition, alternatively spliced transcripts of RAB7L1 (one of the genes in PARK16) was
characterized, and the relative expression of each transcript correlated with the associated variants.

Presentations & Publications
Vilariño-Güell C, Ross OA, Aasly JO, White LR, Rajput A, Rajput AH, Lynch T, Krygowska-Wajs A, Jasinska- Myga J, Opala G, Barcikowska M, Lee MC, Hentati F, Uitti RJ, Wszolek ZK, Farrer MJ, Wu RM (2010)
An independent replication of PARK16 in Asian samples. Neurology 75; 2248-2249.


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