Director: Dennis W. Dickson, M.D.
Title: Genetics and Molecular Biology of Parkinsonism
Budget End Date: 6/30/2017
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 [1-7] and tau [7, 8]. A major focus of the research 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).
All components of the Udall Center are based in Jacksonville, Florida. The Center Director (CD) is Dr. Dennis W. Dickson. The Center Administrator is Ms. Audrey Strongosky. 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 External Advisory Committee, which meets annually, is composed of individuals with expertise in neurology (Dr. Mark LeDoux), genetics (Dr. Gerr Schellenberg), pathology (Dr. Peter Nelson), as well as education and patient outreach (Dr. Peter Schmidt, National Parkinson Foundation). Core B has strong interactions with the Cores C and D, and it provides patient-related material to Project 1. Core C plays a critical role in screening for mutations in patients from the Core B and performing genotyping for Projects 1 and 2. Core D provides brain tissue for Projects 1 and 2.
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 MAPT and α-synucleinopathies not due to mutations in SNCA, LRRK2, GBA, EIF4G1 or other known genes that cause LB-related PD. This projects builds upon success in using linkage based gene discovery and more recently Next-Generation sequencing to discover novel genes. The project uses both generated sequence data and publicly available data sets for variant selection within the novel genetic loci, for genetic association studies in PD and PSP case-control series collected through Cores B and D. The prevalence of significantly associated variants is assessed in the Genetic Epidemiology of PD Consortium (GEO-PD).
Significant progress has been made in demonstrating mutations in the colony-stimulating receptor 1 (CSF1R) as a cause of both pigmentary orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with spheroids (HDLS), showing that they are a single disease entity. In addition, Project 1 performed whole-genome sequencing on 8 patients from 4 separate families with parkinsonism. In three families (Families B, G and M) the proband was characterized by α-synuclein pathology, while in one family (Family V) the proband died with tau pathology consistent with corticobasal degeneration. Project 1 has discovered a novel gene for a parkinsonian family with dystonia and brain calcification, namely a deletion that spans two genes, SLC20A2 and THAP1.
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”) in a large number of postmortem human brains with either Lewy body disease (LBD) (~700 brains) or PSP (~700 brains). For PSP cases genetic variants are available from the CurePSP supported PSP GWAS. For LBD, genetic variants from published PD GWAS are determined by Core C.
Progress has been made finding genome wide associations with quantitative neuropathologic variables summarized by latent trait variables. This PSP latent trait GWAS identified genetic associations in novel loci not previously identified in PSP case-control GWAS. One locus was significantly associated after Bonferroni correction (9.3x10-8), and five additional SNPs were just above this threshold. The most significant locus, DNM3 – dynamin 3, is a gene expressed at high levels in the CNS. This locus has multiple intronic SNPs that each have strong association with the latent variables, further indicating that DNM3 may indeed play a role in PSP pathology. Ongoing studies will validate these findings in an additional 330 PSP cases.
Core A (Administration CL: Dennis W. Dickson, MD) A new web page has been developed to conform with the requirements spelled out in the Udall center RFA. Educational outreach of the Udall Center included a half day course for professionals, patients, and caregivers co-sponsored by Mayo School for Professional Development. Other educational activities included a full day seminar focusing on non-motor aspects of PD, in particular PD with cognitive impairment and Dementia with Lewy Bodies. Faculty in the Udall Center also participated in informal PD support group activities and formal presentations to mixed audiences, such as a keynote address on Dementia with Lewy bodies at Florida Gulf Coast University and grand rounds on PSP and CBD at University of Michigan. Other education outreach makes use of Mayo Foundation medical education resources on PD and related disorders, including formal didactic courses on molecular pathology of neurodegenerative disorders, a weekly scientific seminar series, and novel social media initiatives (Facebook and YouTube).
Core B (Clinical CL: Zbigniew K. Wszolek, MD) follows families with PD or Parkinsonism with known and unknown genetic mutations. These kindreds have either α-synuclein or tau pathology in autopsies of the index case or at least one other family member. In the last year, Core B has examined members of Family C (a large kindred with α-synuclein patholoy). Field trips were made to family reunions to visit 2 of our largest families (Families C and Arkansas kindred). At those reunions 15 affected family members and 20 newly identyfied family members were examined and blood drawn. Core B has expanded Family V, a large multiplex tauopathy kindred and obtained 6 additional blood samples. Pedigrees have been expanded from families with index cases having autopsy-confirmed parkinsonian tauopathies and 13 blood sampes were collected. Work on other families is ongoing.
Longitudinal studies on previously identified families includes work on families with Parkinsonism and frontotemporal dementia and/or ALS due to GRN, TARDBP, CSF1R, C9ORF72 and EIF4G1. Core B also follows families with dystonia, including an African American family, that led to discovery of two novel dystonia gene mutations Gα(olf)10, and CIZ1 (c.790A>G, p.S264G). Core B maintains collaborations with other Udall Centers, including Johns Hopkins, UW, Miami, and UPenn, especially for longitudinal and genetic studies of PD. 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 C (Genetics CL: Owen A. Ross, PhD) biobanks DNA on patients from Core B and from a network of international collaborators. It screens all clinical samples collected through Core B and pathologic cases through Core D for the most common genetic forms related to Parkinson’s disease (LRRK2 G2019S screening), in addition excluding mutations in the LRRK2, SNCA, VPS35 and EIF4G1 genes in samples with a dominant family history and excluding PARKIN, PINK1 and DJ-1 mutations in families with an apparent recessive form of disease or an early-onset age at initial symptom (defined as <45 years of age). All DNA is extracted and labeled with unique identifiers and pedigrees ID numbers that the genetic data is appended to. In addition to traditional Parkinson’s disease genes, Core C has been instrumental in investigating the role of other neurodegeneration-related genes and examining a possible role in Parkinsonism (e.g. TARDBP, FUS and C9orf72) identifying a patient with Parkinson’s disease who harbored a mutation in the TARDBP gene encoding TDP43.
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. These collections will be used in genetic studies in Projects 1 and 2. In the last 12 months (2013-2014), Core D has collected and processed 167 parkinsonian brains, including 66 PSP, 38 LBD, 15 CBD, and 15 MSA. Of the 167 brains, 30 percent have a family history of neurodegenerative disease. Other less common diagnoses include FTLD, Pick’s disease, Perry syndrome and vascular parkinsonism. The average age of the cases is 74 years and there are 94 men and 73 women. Most are white (n=1565), but there were 5 Hispanic, 4 Asians and 2 Pacific Islanders. The brains have minimal Alzheimer type pathology (Braak NFT stage III and Thal amyloid phase 2).
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 dementia with Lewy bodies. 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.
Ogaki K, Ross OA. Chromosome 22q11.2 deletion may contain a locus for recessive early-onset Parkinson's disease. Parkinsonism Relat Disord. 2014 Sept; 20:945-6. PMCID: PMC4143462.
Siuda J, Jasinska-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodière EL, Scarffe LA, Dawson VL, Ross OA, Springer W, Dawson TM, Wszolek ZK. Early-onset Parkinson's disease due to PINK1 p.Q456X mutation - Clinical and functional study. Parkinsonism Relat Disord. 2014 Sep 2.
Montine TJ, Koroshetz WJ, Babcock D, Dickson DW, Galpern WR, Glymour MM, Greenberg SM, Hutton ML, Knopman DS, Kuzmichev AN, Manly JJ, Marder KS, Miller BL, Phelps CH, Seeley WW, Sieber BA, Silverberg NB, Sutherland M, Torborg CL, Waddy SP, Zlokovic BV, Corriveau RA; For the ADRD 2013 Conference Organizing Committee. Recommendations of the Alzheimer's Disease-Related Dementias Conference. Neurology. 2014 Aug 26;83(9):851-860. PMCID: PMC4155046
Fujioka S, Boeve BF, Parisi JE, Tacik P, Aoki N, Strongosky AJ, Baker M, Sanchez-Contreras M, Ross OA, Rademakers R, Sossi V, Dickson DW, Stoessl AJ, Wszolek ZK. A familial form of parkinsonism, dementia, and motor neuron disease: A longitudinal study. Parkinsonism Relat Disord. 2014 Aug 19. PMID: 25175602
Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW,
Wszolek ZK, Pandey A, Dawson TM, Dawson VL.
Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 2014; 157:472-485. PMCID: PMC4040530
The Udall Center at the Mayo Clinic in Jacksonville, Florida 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 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. The Center brings established investigators in complementary areas of research to the task of understanding how tau is related to not only tau-related, but also α-synuclein- related parkinsonian disorders.
Last updated February 10, 2015