Director: Dennis W. Dickson, M.D.
Title: Genetics and Molecular Biology of Parkinsonism
The Udall Center for Excellence in Parkinson's Disease Research at the Mayo Clinic is an integrated, multi-disciplinary research program of neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the “Genetics and Molecular Biology of Parkinsonism.” The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section and longitudinal studies of Parkinson disease (PD) and dementia with Lewy bodies (DLB) for the clinical material used in the research projects, as well as strong institutional commitment to PD research through faculty research funds, an invited speaker seminar series, sponsorship of Movement Disorder fellowships and pilot research grants, as well as generous support for faculty travel to promote inter-institutional collaborations. The research proposed in is highly synergistic and there is a wide range of expertise and scientific background of the members of the Udall team. The work builds upon highly successful and productive cores that have been working together for over a decade. Success of the Mayo Clinic Udall Center has been based upon generous sharing of resources and data.
The Udall Center is based in Mayo Clinic Jacksonville (MCJ). Dennis W. Dickson, MD has been the Center Director for the last eight years. He is assisted by the Center Administrator, Audrey Strongosky, who has extensive experience in organizing clinical trials in the Movement Disorder Section as well as a history of outreach and education to Parkinsonian patients and caregivers. Administrative support is also provided by Mr. Jeffrey Scheffel, who chairs the Department of Research Administration. The CD is assisted by an administrative secretary, Beth Marten, who is also the MCJ Brain Bank coordinator. Scientific oversight is from frequent meetings of the members of the Executive Committee, made up of the project leaders (PL) and core leaders (CL), as well as the center administrator and the educational liaison, Dr. Ryan Uitti (Figure 1).
The proximity of all investigators assures frequent formal and informal interactions that will bond together a cohesive investigative team. Advice and critiques are offered to the CD by the External Advisory Committee, which meets annually and is composed of individuals with expertise in neurology, genetics, pathology, cell biology and pharmacology. The Clinical Core has strong interactions with the Neuropathology and Genetic Cores, and it provides patient-related material to Projects 1 and 2. The Neuropathology Core also provides patient-related material to Projects 1 and 2, as well as expertise in biochemical studies of tau protein provided by Shu-Hui Yen, PhD. The Genetic Core plays a critical role in screening for mutations in patients from the Clinical Core and is designing and assisting Projects 1 and 2 with genetic analyses that are critical to their scientific mission.
The research in this center is highly synergistic and capitalizes on the wide range of expertise and scientific background of the members of the Udall team. Each member of the team brings unique knowledge and skill sets to the mission, and together we are greater than the sum of the parts. Of the more than 400 publications by the Udall key personnel in the last 5-years, 101 were publications that had two or more Udall Center investigator as co-authors (15 papers were shared by 3 or 4 of the investigators). The strongest collaborative bond in the last 5 years was between genetics and both neurology and neuropathology, attesting to the strong translational commitment of the Mayo Clinic Udall Center. It is worth noting, that the Udall Center fosters new collaborations between two highly successful and productive geneticists with expertise in Parkinsonism (Owen A. Ross) and frontotemporal degenerations and Parkinsonian tauopathies (Rosa Rademakers).
This Center has two projects and four cores, with interactions illustrated in Figure 1
Project 1 “Understanding the role of MAPT in Parkinsonian disorders”
Rosa Rademakers, PhD
Aims to identify disease-associated genetic variation within the MAPT locus for two leading parkinsonian disorders, PD and PSP. The research will characterize the prevalence and effect size, and determine the functional consequences of the associated variants on MAPT mRNA and protein. The project will use targeted next-generation sequencing for variant discovery followed by genetic association studies in our extensive PD and PSP case-control series collected through Cores B and D. As Project 1 identifies significantly associated MAPT variants they will be further studied regarding influence of α synuclein and tau pathology in collaboration with Project 2.
Project 2 “Genetic determinants of α-synuclein and tau pathology in Parkinsonism”
Dennis W. Dickson, MD
Aims to determine the role that common genetic variants play in α-synuclein and 4R tau related parkinsonism by generating quantitative traits using digital imaging on a large number of postmortem human brains with either Lewy related pathology (~700 brains) or PSP (~700 brains), all derived from one center, MCJ and reviewed by one neuropathologist. The α synuclein and 4R tauopathy cases will subgrouped using unbiased statistical methods (e.g., hierarchical cluster analysis based upon digital imaging data) in addition to clinical and neuropathologic diagnostic categories. For all brains, genetic variants in genes that have been implicated by meta-analyses of PD genome wide association studies (GWAS) and a recently completed PSP GWAS will be determined from brain-derived DNA by Core C. Worth noting is that over half of the PSP cases will have complete genomic genotyping, since they have been included in the PSP GWAS.8
Core A: Administrative Core
Dennis W. Dickson, MD
Derives support and advice from the Executive Committee as well as internal advisors (quarterly meetings) and external advisors (annual meetings of the External Advisory Committee). The administrator (Audrey Strongosky) assists in compliance with Institutional Review Board IRB) and Mayo Biospecimen Committee policies, grants management, reporting and compliance with NINDS, as well as facilitating interactions with other Udall Centers. Core A coordinates educational activities of the Udall Center for patients, trainees and professionals, in part by tapping Mayo Foundation supported medical education resources, including formal didactic courses on molecular pathology of neurodegenerative disorders and regular scientific seminar series. Core A maintains the Udall internet web page, which is linked to other Mayo Clinic resources on Parkinsonism.
Core B: Clinical Core
Zbigniew K. Wszolek, MD
Follows more than 800 established families with PD or a Parkinsonism with known and unknown genetic mutations. Most these kindreds have Parkinsonism associated with either α-synuclein or tau accumulation. In some families (e.g., those with LRRK2 mutations) mixed pathology is present and in others pathological confirmation needs to be established. Core B will support Project 1 and Project 2 by recruitment of new cases of familial or sporadic PD and PSP. If meaningful therapeutics are discovered in Project 3, a collection of families followed by Core B will be of paramount importance to test therapies in affected and presymptomatic family members. Core B supports Cores C and D by providing DNA samples and arranging for autopsies or transfer of pathological specimens. Core B will also serve as a resource for other Udall Centers and will collaborate with Clinical Cores of other Udall Centers that also have clinical components by collecting cognitive data on our patients using Common Date Elements to promote sharing of data. Core B actively recruits under-represented minorities. The goal for Core B is to contribute to gene discoveries on families with Parkinsonism and to assist in clinical studies by Center investigators or other collaborating Udall Centers.
Core C: Genetic Core
Owen A. Ross, PhD
Provides a valuable resource in biobanking of DNA and genetic screening for all samples collected through Cores B and D. The core screens known genetic variants that are pathogenic and highly penetrant in families studied by Core B and also examine variants that influence risk of PD and related parkinsonian disorders. Core C supports Core D by screening for mutations in new brain specimens and the existing collection of cases with a positive family history of Parkinsonism for novel gene discoveries implicated in familial PD, such as EIF4G1 and VPS35, which will help characterize the pathology associated with these genetic forms of PD. Core C will organize and distribute samples for components of the genetic studies in Projects 1 and 2. In addition, as Core B expands large Parkinsonian families without a known genetic cause, Core C will facilitate exome sequencing to characterize the genetic variation within the family which can be instrumental in identifying novel genes for PD and related disorders. Core C will assist other Udall Centers with genetic analysis as it has done in the past with The Feinstein Institute for Medical Research North Shore-Long Island Jewish Heath System, Manhasset, NY. Core C will provide genetic support for PD and Parkinsonism cases collected by Core B with additional cognitive instruments that will be analyzed by other Udall Centers (University of Pennsylvania, University of Washington, and University of California, Los Angeles Udall Centers), Core C will also provide genetic support for cases collected by the John Hopkins University Udall Center.
Core D: Neuropathology Core
Dennis W. Dickson, MD
The Neuropathology Core will characterize and subtype the Parkinsonian brains collected through efforts of Core B, as well as other referrals (e.g., patients of Dr. Langston at The Parkinson Institute and of Dr. Pahwa at the University of Kansas). Core D is also the brain bank for The Society for PSP (CurePSP, Inc.) and has a large and growing collection of PSP and MSA brains, the latter being a recent initiative of Cure PSP. Core D has a large and growing collection of dementia with Lewy body cases from the Mayo Alzheimer Disease Research Center (ADRC) and funding for DLB research by the Mangurian Foundation. In addition, brains are received from wide ranging referrals, given the recognition among the general public and in the Lewy Body Dementia Association (LBDA) and its associated blogs that this is an area of our expertise and interest. These collections will be used in genetic studies in Project 1 and are the major focus of research in Project 2. Expertise in Core D on biochemical characterization of brain tau from years of research on tau by Dr. Shu-Hui Yen is also at the disposal of the research projects for their proposed studies. The former will be used in Projects 1 and 2 to characterize functional variants in MAPT and genetic variants that may associate with tau biochemical properties.
Leadership in PD research
The members of the Mayo Clinic Udall Center for Excellence in Parkinson Disease Research have taken the lead in three major areas of PD research – clinical genetics, molecular genetics and neuropathology of PD and tauopathies. The leader of Core B, Dr. Wszolek, was at the forefront of clinical recognition that PD could be familial, and his collection of a large number of multi-incident families with parkinsonism contributed to discovery of mutations in MAPT in frontotemporal dementia and parkinsonism linked to chromosome mutations in DCTN1 in autosomal dominant early onset PD with depression and hypoventilation (Perry’s syndrome), and most importantly to mutations in LRRK2 in familial autosomal dominant PD, the most common cause of genetically determined PD. The leader of Core C, Owen A. Ross, has contributed to the discovery of mutations and common variants in a number of genes relevant to PD, including LRRK2, SNCA, GBA, DCTN1 and MAPT, while the leader of Project 1, Rosa Rademakers has contributed to discovery of genes and gene variants that cause or contribute to frontotemporal dementia, amyotrophic lateral sclerosis and Parkinsonian tauopathies. The CD and leader of Core D has made significant contributions to the neuropathology of a wide range of neurodegenerative disorders that produce Parkinsonism and dementia. He has participated in consensus committees on neuropathologic criteria for the most common neurodegenerative diseases, including AD, DLB, PSP, FTDP-1749 and CBD. He played a key role in formulating data elements for neuropathology in the National Alzheimer Coordinating Center (NACC) database, which has been incorporated into Common Data Elements for PD. He has actively participated in annual Udall Centers meetings and chaired sessions on clinicopathologic correlates (Boston 2002), neuropathologic criteria for PD (Durham, NC 2003), brain banking (Washington 2004) and most recently critical evaluation of the Braak PD staging scheme (with Dr. Heiko Braak in Pittsburgh 2007). He has been the chair of neuropathology subgroups for the NINDS initiative to create common data elements (CDE) for both PD and frontotemporal degeneration. The goal of the CDE initiative is to foster multi-center collaborative research projects and for merging of datasets across a wide range of studies. He has contributed to defining neuropathologic criteria and minimal clinical and pathologic data elements for a new NINDS initiative on GWAS of pathologically confirmed PD (PI Jeff Vance, University of Miami). The impact of these efforts by Udall Center leaders is considerable, as identification of genes that cause PD are the basis for understanding fundamental aspects of disease pathogenesis, which is the foundation for rational therapeutics.
Among the major achievements that the Udall Center can claim are discovery of the most common genetic cause of late-onset, autosomal dominant PD – mutations in leucine-rich repeat kinase 2 (LRRK2)1; discovery of a rare genetic cause of rapidly progressing PD associated with depression and hypoventilation (Perry syndrome) – mutations in dynactin p150 (DCTN1)2; identification of genetic variants in the α synuclein gene (SNCA) that are risk factors for PD; discovery that incidental Lewy body disease is pre-clinical PD in most cases, but in some cases perhaps pre-clinical dementia with Lewy bodies (DLB)3; validated neuropathologic criteria for DLB4; and developed of novel α-synuclein constructs that produce Lewy-like aggregates in cell culture permitting a valuable system for drug screening that will translate into new disease modifying therapies for PD and other α-synucleinopathies5. Most recently, two new genes for autosomal dominant PD have been discovered - eukaryotic translation initiation factor 4 gamma (eIF4G1)6 and vesicular sorting protein 35 (VPS35)7, in which sequence variants are present in familial PD and Lewy body disease, but not in control subjects.
Brain and Tissue Bank:
The findings from the Mayo Clinic Udall Center have direct relevance to PD in that our goals are to identify genes that cause PD or are risk factors for PD. Subsequent studies aim to understand how these genes lead to neurodegeneration, what can be done to detect these changes at the earliest stages of PD and how these genes might be used as targets for novel therapies for PD.
Last updated March 20, 2013