Director: Dennis W. Dickson, M.D.
Title: Genetics and Molecular Biology of Parkinsonism
The Udall Center is an integrated, multi-disciplinary research program on the “Genetics and Molecular Biology of Parkinsonism.” The Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Division, longitudinal studies of Parkinsonian disorders and a large and growing brain bank of neurodegenerative disorders. Our Center has played a leading role in family-based studies and has contributed to major discoveries of the genetic basis of familial Parkinsonism, including genes that cause Parkinsonism associated with α-synuclein (SNCA) and tau (MAPT). A major focus of the research in the Center is on these two molecular forms of Parkinsonism, given the increasingly compelling evidence from biological, neuropathologic and genetic studies of the importance of both α-synuclein and tau in Parkinson’s disease (PD).
The Mayo Clinic Udall Center has been an indispensable member of the community of Udall Centers as well as a collaborator on multiple fronts in the battle to understand and develop better ways to diagnose and treat PD. The Udall Center is highly innovative and original in that it addresses genetic basis of PD and Parkinsonian tauopathies, focusing on the role of tau in Progressive supranuclear palsy (PSP) and the increasingly recognized role of tau in PD. The clinical, genetic and pathologic studies capitalize on inherent strengths of the Udall Center investigators and unique clinical, genetic and pathological resources that have been built over the years due to the devotion of Center investigators to better understanding PD and related disorders. The Center also brings established investigators in complementary areas of research to the task of understanding the genetic basis of PD and Parkinsonian tauopathies.
All research components of the Udall Center are based in Jacksonville, Florida; the Center also leverages core Mayo Clinic resources, particularly in the Division of Biomedical Statistics as well as Mayo Foundation educational resources (Rochester, Minnesota). The Center Director (CD) is Dr. Dennis W. Dickson. He is assisted by the Center Administrator, Ms. Audrey Strongosky, who has extensive experience in organizing clinical trials in the Mayo Movement Disorder Section as well as a history of outreach and education to Parkinsonian patients and caregivers. She has first-hand knowledge of Institutional Review Board and Mayo Biospecimen Committee procedures and has assisted in obtaining material transfer agreements for sharing of biological specimens and data with outside investigators. Administrative support is also provided by Department of Research Administration, and by an administrative secretary, Ms. Beth Marten, who is also the 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. The proximity of all investigators assures frequent formal and informal interactions. Advice is provided by the External Advisory Committee, which meets annually and is composed of individuals with expertise in neurology (Dr. Mark LeDoux), genetics (Dr. Gerry Schellenberg), pathology (Dr. Peter Nelson), as well as education and patient outreach (Dr. Peter Schmidt, National Parkinson Foundation). The CD oversees the activities of the Center and reports to the NINDS with the assistance of the Center Administrator.
The research at the Mayo Udall Center is highly synergistic and capitalizes on the wide range of expertise and scientific background of the members of the Center. 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 175 publications listed on PubMed by the Udall Center key personnel in the last two years, 69 were publications (39%) that had two or more Udall Center investigator as co-authors (18 papers were shared by 3 or 4 of the investigators). Strong collaborative bonds between neurology and genetics, neurology and pathology, and between pathology and genetics, attest to the translational commitment of the Mayo Clinic Udall Center. There is also an interconnected focus on molecular biology of Parkinsonism and other neurodegenerative disorders. It is worth noting, that this 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).
Project 1: Identification of novel Parkinsonian genes by whole-genome sequencing (PL: Rosa Rademakers, PhD) aims to determine the genetic basis of parkinsonian tauopathies not due to the tau gene (MAPT) and α-synucleinopathies not due to mutations in synuclein (SNCA), LRRK2, GBA, EIF4G1 or other known genes that cause Lewy Body (LB)-related PD. This projects builds upon considerable success in using linkage based gene discovery and more recently Next-Generation sequencing to discover novel genes. Notable examples of the former is C9ORF72 mutations in FTD/ALS linked to chromosome 9 and CSF1R mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). An example of the latter is discovery of mutations in VPS35 in familial PD. This project will use multi-incident families expanded and characterized by Core B with at least an index case with known tau or α-synuclein pathology at autopsy. In addition, the project will use both generated sequence data and publicly available data sets for variant selection within the novel genetic loci, for genetic association studies in our extensive PD and PSP case-control series collected through Cores B and D. The global prevalence of significantly associated variants can be further assessed through other collaborative efforts, such as the multinational Genetic Epidemiology of PD consortium (GEO-PD). As Project 1 identifies novel genes and significantly associated variants, they will be further studied regarding influence on intermediate pathological phenotypes in collaboration with Project 2.
Project 2: Genetic determinants of α-synuclein and tau pathology in Parkinsonism (PL: Dennis W. Dickson, MD) aims to determine the role that common genetic variants play in PD and PSP by generating quantitative traits (“intermediate phenotypes”) using digital imaging on a large number of postmortem human brains with either Lewy body disease (LBD) (~700 brains) or PSP (~700 brains), all derived from one center, MCJ, and reviewed by one neuropathologist. For all brains used in Project 2, genetic variants in genes that have been implicated by meta-analyses of PD GWAS and autopsy-confirmed PD and PSP GWAS will be determined by Core C. Worth noting is that over half of the PSP cases (~600) will have complete genomic genotyping and a number (~200) of the LBD will also, since they were included in the PSP and PD autopsy GWAS.
Core A: Administration (CL: 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). Core A has a designated administrator (Audrey Strongosky) to assist 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. Dr. Uitti serves as the educational liaison for Core A, and coordinates educational activities of the Udall Center for patients, trainees and professionals. Education outreach makes the most of Mayo Foundation medical education resources on PD and related disorders, including formal didactic courses on molecular pathology of neurodegenerative disorders, a regular scientific seminar series, and novel social media initiatives (Facebook and YouTube). Core A maintains the Udall internet web page (http://www.mayo.edu/research/centers-programs/morris-k-udall-parkinsons-disease-center/overview), which is linked to other Mayo Clinic resources on PD. Educational activities build upon the considerable success in attracting bright young physicians and scientists to study PD and related disorders at MCJ.
Core B: Clinical (CL: Zbigniew K. Wszolek, MD) will follow some of the more than 850 established families with PD or Parkinsonism with known
and unknown genetic mutations. Most these kindreds have either α-synuclein or tau pathology in autopsies of the index case
or at least one other family member. In some families (e.g., those with LRRK2 mutations), mixed pathology is present and in others pathological confirmation has yet to be established. Core B will support Project 1 by recruitment of new cases of familial or sporadic PD and PSP. Core B supports Project 2 by indirectly arranging for autopsies on PD and PSP patients. Core B supports Cores C by providing DNA samples from Mayo PD patients and controls, and DNA from its international network of collaborators. Core B arranges for autopsies or transfer of pathological specimens to Core D. Core B serves as a facilitator of collaboration with other Udall Centers, especially those Udall Centers with significant clinical
components, and sharing of clinical data using Common Data Elements (CDE). Physicians and study coordinators of Core B play a key role in patient and caregiver educational efforts through established support groups for PD and other related
disorders. Core B actively recruits under-represented minorities. The overarching 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: Genetics (CL: Owen A. Ross, PhD) provides a valuable resource in its role as a biobank for DNA on patients from Core B and from a network of international collaborators. It screens for genetic mutations that are known to cause PD in samples
collected by Core B. Core C also screens known genetic variants that are pathogenic or highly penetrant in families studied by Core B, and also examine variants that influence risk of PD and related Parkinsonian disorders. Core C provides support to Core D by screening for mutation status in cases, targeted especially on brains of individuals with a positive family history of
Parkinsonism or those that have atypical pathologic findings. Core C identifies cases to help characterize the pathology associated with these new genetic forms of PD. Core C provides genotype data for the genetic studies in Projects 1 and 2.
Core D: Neuropathology (CL: Dennis W. Dickson, MD) characterizes and subtypes the Parkinsonian brains collected through efforts of Core B, as well as other referrals (e.g., cases from The Parkinson Institute, Sunnyvale, CA). Core D is also the brain bank for CurePSP, and has a large and growing collection of PSP and MSA brains, the latter being a recent initiative of Cure PSP. Core D also has a large and growing collection of brains with Lewy-related pathology, including cases with dementia with Lewy body cases (DLB), PD and Parkinson’s Disease with Dementia (PDD). In addition, the Mayo Clinic is receiving wide ranging referrals for brain donation, given the recognition among the general public as well as by the Lewy Body Dementia Association (LBDA) and its associated internet blogs. These collections are used in genetic studies in Projects 1 and 2.
The members of the Mayo Clinic Udall Center have taken the lead in several areas of PD research – clinical genetics (Cores B and C), molecular genetics (Core C and Project 1), and neuropathology (Core D and Project 2). 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 FTDP-17, mutations in DCTN1 in autosomal dominant early onset PD with depression and hypoventilation (Perry’s syndrome), and most importantly, to mutations in the gene for leucine rich repeat kinase 2, LRRK2, in familial autosomal dominant PD. The latter is the most common cause of genetically determined PD. The leader of Core C, Dr. 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, EIF4G1, VPS35 and MAPT, while the leader of Project 1, Dr. Rosa Rademakers, has contributed to discovery of genes and gene variants that cause or contribute to frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and tauopathies. Most recently, she and her team have discovered the most common genetic cause of FTD/ALS linked to chromosome 9 (C9ORF72), and to mutations in CSF1 receptor (CSF1R) in hereditary leukoencephalopathy with spheroids, which can present as an atypical parkinsonian disorder or as FTD.
The Center Director (Dr. Dickson) 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 PD, AD, DLB, PSP, FTDP-17 and corticobasal dementia (CBD). He played a key role in formulating data elements for the NINDS Common Data Elements for PD (http://www.commondataelements.ninds.nih.gov/PD.aspx). He has actively participated in annual Udall Centers meetings and chaired sessions on clinicopathologic correlates neuropathologic criteria for PD, brain banking, and critical evaluation of the Braak PD staging scheme. He has been the chair of neuropathology subgroups for the NINDS initiative to create CDE for both PD and FTD. The goal of the CDE initiative is to foster multi-center collaborative research projects and to facilitate merging of datasets across a wide range of studies. He contributed to defining neuropathologic criteria and minimal clinical and pathologic data elements for a collaborative 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.
The Mayo Udall Center has a number of collaborations with other Udall Centers and PD researchers. Core B has collaborations with all of the Udall Centers with significant clinical projects or cores, including the University of Washington (UW), University of Pennsylvania (Penn), Johns Hopkins University, and the Feinstein Institute for Medical Research North Shore-Long Island Jewish Health System (North Shore University). These collaborations are mutually beneficial. For Udall centers focusing on cognitive and genetic aspects on PD (UW and Penn), Cores B and C will share cognitive data and DNA for correlative and genetic studies. Several of these Udall Centers have agreed to assist Core B in determination of multiple-affected familial PD kindreds for further expansion and characterization by Core B. They also agree to assist in evaluation of members of Core B families that may reside in their geographic area. Core C is collaborating on genetic characterization of PD patients followed in neuroimaging studies at North Shore University. Core D has provided brain specimens (LRRK2 mutation cases) to Udall Center investigators at Columbia University and at Johns Hopkins University. Core D is collaborating with the Udall Center at University of Miami on the NINDS-sponsored autopsy PD GWAS. In addition to Udall Center collaborations, other collaborative efforts of Cores B and C worth noting are involvement in the consortium for GWAS of autopsy-verified PD led by Dr. Tatiana Foroud (University of Indiana), and two programs to develop induced pluripotent stem cells from fibroblasts of patients with known mutations in PD-causing genes at Harvard University (Dr. Ole Isacson) and Johns Hopkins University (Dr. Ted Dawson), as well as collaborations with PD researchers at UCLA (Dr. Marie-Françoise Chesselet). Core B collaborates with an additional 55 national and international scientists, all approved by the Mayo IRB Committee.
The Mayo Clinic is one of the most recognized names in the area of patient education. The Udall Center will capitalize on resources of the Mayo Foundation for Medical Education and Research, including its recent foray into social media, establishing a Mayo Clinic presence on Facebook, YouTube, Twitter, as well as on-line blogs and Podcasts (see Core A for details). Core B investigators and support personnel have on-going patient outreach efforts in the form of family support groups for PD, restless legs syndrome and dystonia. There are also support groups by our colleagues in Psychiatry and Psychology (Dr. Tanis Ferman) for DLB. Our center investigators have considerable strength in training successful graduate and post-graduate fellows, as well as mentoring clinical fellows. These fellows play key roles to the research efforts in the Udall Center and contribute significantly to peer-reviewed publications, as well as reviews and book chapters. As part of their training, they are required to present their research at national and international meetings. Several of these young investigators have also presented their work in the form of poster presentations at the annual Udall Centers meetings.
Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations. Sundal C, Fujioka S, Van Gerpen JA, Wider C, Nicholson AM, Baker M, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern
J, Tselis A, Swerdlow RH, Miller BB, Borjesson-Hanson A, Uitti RJ, Ross OA, Stoessl AJ, Rademakers R, Josephs KA, Dickson
DW, Broderick D, Wszolek ZK. Parkinsonism Relat Disord. 2013 Oct;19(10):869-77. PMID: 23787135
Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Kouri N, Carlomagno Y, Baker M, Liesinger AM, Caselli RJ, Wszolek ZK, Petrucelli L, Boeve BF, Parisi JE, Josephs KA, Uitti
RJ, Ross OA, Graff-Radford NR, Deture MA, Dickson DW, Rademakers R. Acta Neuropathol. 2013 Oct 12. PMID: 24121548
Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD)
consortium. Heckman MG, Soto-Ortolaza AI, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Carr J, Chartier-Harlin
MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Boczarska-Jedynak
M, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez
E, Nilsson C, Opala G, Park SS, Petrucci S, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V,
Theuns J, Tomiyama H, Uitti RJ, Valente EM, Van Broeckhoven C, van de Loo S, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt
K, Wszolek ZK, Wu RM, Hentati F, Farrer MJ, Ross OA; on behalf of the Genetic Epidemiology of Parkinson's Disease (GEO-PD)
Consortium.Mov Disord. 2013 Aug 2. PMID: 23913756
TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Josephs KA, Knopman DS, White CL 3rd, Caselli R, Mackenzie IR, Miller BL, Boczarska-Jedynak M, Opala G, Krygowska-Wajs A, Barcikowska M, Younkin SG, Petersen RC, Ertekin-Taner N, Uitti RJ, Meschia JF, Boylan KB, Boeve BF, Graff-Radford NR, Wszolek ZK, Dickson DW, Rademakers R, Ross OA. Mol Neurodegener. 2013 Jun 21;8:19. PMID: 23800361 Free PMC Article
Last updated November 6, 2013