Udall Center - Mayo Clinic Jacksonville

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Director: Dennis W. Dickson, M.D.

Title: Genetics and Molecular Biology of Parkinsonism

Website: http://mayoresearch.mayo.edu/mayo/research/udall_center/

 

Central Theme

The NINDS Udall Center at Mayo Clinic in Jacksonville, Florida, focuses on understanding two molecular forms of Parkinsonism, namely those associated with α-synuclein and tau pathology, and their associated manifestations as synucleinopathies (i.e. Parkinson’s disease (PD), Parkinson disease dementia, PDD; dementia with Lewy bodies (DLB); multiple system atrophy, MSA); or tauopathies (i.e. progressive supranuclear palsy, PSP; corticobasal degeneration, CBD).

Center Structure

The Udall Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section with its longitudinal studies of Parkinson’s disease (PD) and a focus on the clinical genetics of familial Parkinsonism, a large brain bank of Parkinsonian disorders and strong institutional commitment to PD research and education. The Mayo Udall Center consists of two research projects and four supportive cores.

Project 1: Identification of novel parkinsonian genes by whole-genome sequencing (Rosa Rademakers, PhD) uses whole-genome sequencing in our unique collection of families with neurodegeneration to identify novel genes for Parkinsonian ɑ-synucleinopathies (Aim 1) and tauopathies (Aim 2). Families are selected based on the availability of DNA samples from at least 3 affecteds, preferentially including an affected cousin-pair, autopsy confirmation of Lewy-body pathology or tau pathology, and exclusion of mutations in all known autosomal dominant PD genes and the microtubule associated protein tau gene, MAPT. Novel variants will be prioritized based on the type of mutation and analyzed in a strictly defined manner. To determine whether rare and common variants in novel causal Parkinsonian genes confer risk to the general population of PD and PSP patients, in-depth association studies of novel parkinsonian genes will subsequently be performed (Aim 3). Coding variants identified by candidate gene sequencing combined with haplotype-tagging variants across the candidate gene loci selected from public databases will be included. Significantly associated variants will be further studied by assessing their influence on gene and protein expression, and the potential interaction with tau and ɑ-synuclein biology. The discovery of novel genes and genetic risk factors will contribute to a better understanding of the disease mechanism associated with tau and ɑ-synuclein dysfunction in Parkinsonian disorders. Moreover, the identification of novel Parkinsonian genes will further allow the development of novel etiologic and symptomatic disease models in which new therapies can be evaluated..

Project 2: Genetic determinants of a-synuclein and tau pathology in parkinsonism (Dennis Dickson, MD) will use intermediate pathologic phenotypes to explore associations with genetic variants in PSP and Lewy body disease (LBD). We will use MAPT, as well as non-MAPT single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) of PSP and PD, following up with functional MAPT variants identified in Project 1. In Aim 1, pathologic phenotypes, including tau burden and microgliosis, will be assessed in several brain regions in pathological subgroupings of PSP, and estimated latent trait variables will be constructed from semi-quantitative lesion scores. Studies in Aim 2 will assess association of intermediate pathologic phenotypes with gene variants in PSP. Each SNP will be tested for association in more than 700 PSP cases against 5 primary pathologic phenotypes. Aim 3 studies will generate intermediate pathologic phenotypes for LBD, including measures of ɑ-synuclein, amyloid beta (Aβ), and tau burden; tyrosine hydroxylase immunohistochemistry; microgliosis and Lewy body (LB) counts in multiple brain regions. We will estimate latent trait variables underlying the semi-quantitative scores of LBs, plaques and tangles as in Aim 1. Aim 4 will assess association of intermediate pathologic phenotypes with gene variants from the collaborative Autopsy-Confirmed Parkinson Disease Genetics Consortium study [Beecham et al (2015) Neurology 84: 972-980). SNPs will be identified as top hits from the autopsy PD GWAS. Each SNP will be tested for association with 9 intermediate phenotypes in more than 700 LBD cases. Finally, Aim 5 will assess MAPT functional variants in PSP and LBD. Ultimately, genetic and phenotypic data on a large number of PSP and LBD brains will not only provide mechanistic insight into the molecular underpinnings of parkinsonian disorders, but also serve as a resource for the field. Results of this project will provide insights into the molecular underpinnings of parkinsonian disorders.

The Center draws upon strengths of clinical genetics of familial parkinsonian disorders conducted by the Clinical Core (Zbigniew Wszolek, MD) and on the characterization of parkinsonian brains collected by the Neuropathology Core (Dr. Dickson).  The Genetic Core (Owen Ross, PhD) is tightly linked to the other cores and to the two research projects. Through the Administrative Core (Dr. Dickson), the Center also collaborates with other Udall Centers, promotes career enhancement of young investigators, and actively participates in outreach to the local patient and caregiver community.

Research at the Mayo Udall Center addresses research priorities from NINDS PD2014, including:

  • Translational Research Recommendation 8: Develop a thorough understanding of targets and pathways associated with pathogenesis and pathophysiologic mechanisms of PD with emphasis on those validated by human genetics and biology.
  • Basic Research Recommendation 7: Develop a more detailed understanding of the genetic basis of PD.

 

Publications Available from the Mayo Clinic Jacksonville Udall Center


Resources Available

The brain bank at Mayo Clinic houses fixed and frozen brain specimens of Parkinsonian disorders, including over 1200 frozen brains with Lewy bodies, over 1000 with PSP, over 160 with CBD and over 130 with MSA.


Public Health Statement

The cause of Parkinson’s Disease (PD) and related disorders is complex and largely unknown. The disease may seem to run within families (“familial”) or appear without prior family history (“sporadic”). The discovery of several candidate genes linked to parkinsonian disorders has provided the means to study familial disease. Over the last several years, there has been a veritable torrent of information on the human genome, as well as rapid development of precise methods to explore the genetics of parkinsonisms.  The focus of the Mayo Clinic Udall Center is discovery of mutations (i.e. changes) in genes that cause familial PD and parkinsonian syndromes as well as genetic variants that contribute to risk of sporadic PD, and characterizing neuropathology of neurodegenerative disorders that produce parkinsonism.