In collaboration with Dr Karen Marder (Sergievsky Center and Taub Institute, Columbia University) and Dr. Stanley Fahn (Neurology, Columbia University), we are studying families and individuals with Parkinson’s disease (PD) using molecular genetics. The clinical collection that we are using comprises PD families, early-onset PD patients (<50 years), and late-onset PD patients (> 50 years). PD is heterogeneous, a complex clinical syndrome caused by many genetic and environmental insults. To date, eight major genetic loci have been directly implicated in PD. In families and sporadic PD cases, mutations have been identified in the a-synuclein gene (PARK1), in Parkin, in juvenile and early-onset parkinsonism (PARK2), and in the ubiquitin C-terminal hydrolase I (UCH-L1) gene (PARK5). Although mutations in a-synuclein and UCH-L1 are rare, parkin gene mutations account for many cases of early-onset PD.

Parkin and Early-Onset PD

We are screening the Parkin gene for mutations in 200 early-onset patients to estimate the attributable risk of parkin in early-onset PD and to determine genotype-phenotype correlations.

Among patients with early-onset PD, mutations in the parkin gene are the most frequently reported. However >50% of autosomal recessive early-onset families do not have mutations in the parkin gene. On chromosome 1, PARK6 and PARK7, represent two loci for early-onset PD for which the genes are currently unknown. These loci may contain disease genes that account for a large proportion of early-onset Parkinson’s disease. We plan to screen candidate genes located at PARK6 and PARK7 in early-onset PD cases without Parkin mutations.

Candidate Genes and Association studies in Idiopathic PD and Parkinson’s disease with Dementia

To identify genetic risk factors for idiopathic PD and Parkinson’s disease with dementia we are investigating the role of several candidate genes. In addition to analyzing genes previously identified as genetic risk factors in other neurodegenerative diseases, including Alzheimer’s disease and Progressive Supranuclear Palsy, we are also testing genes that are key components of the ubiquitin-proteasome pathway.

Selected Recent Publications:

• Clark LN, Afridi S, Mejia-Santana H, Harris J, Louis ED, Cote LJ, Andrews H, Singleton A, Wavrant De-Vrieze F, Hardy J, Mayeux R, Fahn S, Waters C, Ford B, Frucht S, Ottman R, Marder K. Analysis of an early-onset Parkinson's disease cohort for DJ-1 mutations. Movement Disorders 2004 Jul;19(7):796-800.
• Chih B, Afridi SK, Clark L, Scheiffele P. Disorder-associated mutations lead to functional inactivation of neuroligins. Human Molecular Genetics 2004 Jul 15;13(14):1471-7.
• Clark, L. N., Poorkaj, P., Wszolek, Z., Geschwind, D. H., Nasreddine, Z. S., Miller, B., Payami, H., Awert, F., Markopoulou, K., D’Souza, I., M.Y. Lee, V., Reed, L., Trojanowski, J. Q., Zhukareva, V., Bird, T., Schellenberg, G. and Wilhelmsen, K. C. (1998) Pathogenic implications of mutations in the tau gene in Pallido-Ponto-Nigral degeneration and related chromosome 17-linked neurodegenerative disorders. Proceedings of The National Academy of Sciences of the United States of America 95: 13103-13107.
• Clark, L. N. and Wilhelmsen, K. C. W. (1998) The genetics of Pick’s disease spectrum and adult onset dementia. In Kertesz, A. and Munoz, D. (eds.): Pick’s disease and Pick complex. John Wiley & Sons, Inc.
• Nasreddine, Z. S., Loginov, M., Clark, L. N., Lamarche, J., Miller, B. L., Lamontagne, A., Zhukareva, V., M.-Y. Lee, V., Wilhelmsen, K. and Geschwind, D. H. (1999) From genotype to phenotype: A clinical, pathological and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Annals of Neurology 45 (6): 704-715.
• Wilhelmsen, K. C. W., Clark, L. N., Geschwind, D. H. and Miller, B. (2000) Mutational analysis of tau in chromosome 17-linked dementia. In Lee, Trojanowski, Buee and Christen (eds) Fatal attractions: Protein aggregates in Neurodegenerative Disorders. Research and perspectives in Alzheimer’s Disease.
• Clark LN, Levy G, Tang M-X, Mejia-Santana H, Ciappa A, Tycko B, Cote LJ, Louis ED, Mayeux R, Marder K (2003) The Saitohin 'Q7R' polymorphism and tau haplotype in multi-ethnic Alzheimer disease and Parkinson's disease cohorts. Neuroscience Letters 347: 17-20.