The Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Mayo Clinic, Jacksonville

Director: Dennis W. Dickson, M.D.

Title: Genetics and Molecular Biology of Parkinsonism

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

Center Theme 

The Udall Center for Excellence in Parkinson 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.  

Center Structure

All components of the Udall Center at Mayo Clinic Jacksonville (MCJ) are based in Jacksonville, Florida.  The Center Director (CD) is Dennis W. Dickson, MD, who has served in this capacity 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.  Additionally, Beth Marten serves as both the Udall Center Administrative Secretary as well as the Coordinator for the MCJ Brain Bank.  Scientific oversight for the center is provided by frequent meetings of the Executive Committee, comprised of the project leaders (PL) and core leaders (CL), as well as the Center Administrator and the Educational Liaison, Dr. Ryan Uitti.  This Center has three projects and four cores as detailed below:

Project 1 (PI: Rosa Rademakers, PhD), “Understanding the role of MAPT in Parkinsonian disorders” aims to identify disease-associated genetic variation within the MAPT locus for two leading parkinsonian disorders, Parkinson’s disease (PD) and Progressive Supranuclear Palsy (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 (PI: Dennis W. Dickson, MD), “Genetic determinants of α synuclein and tau pathology in Parkinsonism” 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 be 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 were included in the PSP GWAS.

Project 3 (PL: Leonard Petrucelli, PhD), “Identification and testing of novel compounds to treat Parkinsonian tauopathies” aims to conduct high-throughput screens of a library of small-molecules having a high probability of blood brain barrier permeability to identify compounds that selectively bind to soluble tau or to both tau and α-synuclein.  The initial goal is to study tau anti-aggregation binding drugs and later to explore, through other funding mechanisms, drugs that block α synuclein aggregation.  Secondary and tertiary screens will consist of a battery of tests to determine which of the tau-binding compounds reduce tau aggregation in vitro as well as in a primary neuron model of tauopathy that will be developed and characterized.  Finally, preclinical testing will be conducted on the three most promising compounds in mouse models.  By identifying compounds that bind soluble tau and prevent its aggregation, and performing preclinical evaluations of compounds of interest, these studies are expected to advance the discovery of new and effective therapies for the prevention and treatment of Parkinsonian tauopathies and tau-related pathologies in PD and dementia in Parkinson’s disease (PDD).  

Core A (PI: Dennis W. Dickson, MD), Administrative Core 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 a regular scientific seminar series.  Core A maintains the Udall internet web page, which is linked to other Mayo Clinic resources on Parkinsonism.

Core B (PI: Zbigniew K. Wszolek, MD), Clinical Core follows more than 800 established families with PD or a Parkinsonism with known and unknown genetic mutations.  Most of 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 (PI: Owen A. Ross, PhD), Genetic Core 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 examines 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 and the University of Washington Udall Centers). Core C will also provide genetic support for cases collected by the John Hopkins University Udall Center.

Core D (PI: Dennis W. Dickson, MD), Neuropathology will characterize and subtype the Parkinsonian brains collected through the 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 B 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 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.  Core D also assists Project 3 in assessing outcome measures with electron microscopy of filament preparations and neuropathology of animal models, when candidate drugs are identified from high throughput screening efforts.  Expertise on biochemical characterization of brain tau is provided by Dr. Shu-Hui and Dr. Wen-Lang provides electron microscopy expertise to Core D and any of the other Center Projects and Cores. 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, while the latter will be used by Project 3. 

Recent Significant Advances

Among the major achievements that the Udall Center can claim are

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 17,8 mutations in DCTN1 in autosomal dominant early onset PD with depression and hypoventilation (Perry’s syndrome),2 and most importantly to mutations in LRRK2 in familial autosomal dominant PD,1 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,2,9-20 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.21-33 The center director and leader of Core D Dennis 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 Alzheimer’s disease,34 dementia with Lewy bodies,35-36 progressive supranuclear palsy,37 frontotemporal dementia with parkinsonism-1738 and corticobasal degeneration disease.  Dr. Dickson 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 (http://www.commondataelements.ninds.nih.gov/PD.aspx).  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.  In that vein, research in Project 3, holds promise to identify disease modifying therapeutics that target tau (initially, and α-synuclein in later years) for treating at least Parkinsonian tauopathies, but also perhaps PD or PD with dementia.  The leader of Project 3 (Leonard Petrucelli) and the leader of Project 1, Rosa Rademakers, are new to the Mayo Clinic Udall Center.  Dr. Petrucelli brings to the Center exceptional basic science and pharmacologic skills.  His work on the cell biology of processes critical to the pathogenesis of PD and Parkinsonian tauopathies is notable for contributions to understanding chaperone-mediated clearance of abnormally folded proteins.

Available Resources

Brain and tissue bank

• Parkinsonism and controls (including multi-incident families) N=19,257

• Lrrk2 BAC mice (FVB strain)
• Lrrk2 G2019S BAC mice (FVB strain)
• Lrrk2 knock-out mice (C56BL6 strain)
• Lrrk2 G2019S knock-in mice

Plans for the Coming Year

• Collect and expand additional multi-incident PD families.
• Use whole genome sequencing in multi-incident families to discover new PD genes.
• Expand research on preclinical PD (incidental Lewy body disease) and investigate dementia in late stage PD compared to dementia with Lewy bodies.
• Screen inducible cell model of α-synuclein expression for aggregation inhibitors as an effort to develop disease-modifying therapies for PD and other synucleinopathies.

Selected Recent Publications

1. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology, Neuron 2004, 44:601-607
2. Farrer MJ, Hulihan MM, Kachergus JM, Dachsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilarino-Guell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK: DCTN1 mutations in Perry syndrome, Nature genetics 2009, 41:163-165
3. Dickson DW, Fujishiro H, DelleDonne A, Menke J, Ahmed Z, Klos KJ, Josephs KA, Frigerio R, Burnett M, Parisi JE, Ahlskog JE: Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease, Acta Neuropathol 2008, 115:437-444
4. Fujishiro H, Ferman TJ, Boeve BF, Smith GE, Graff-Radford NR, Uitti RJ, Wszolek ZK, Knopman DS, Petersen RC, Parisi JE, Dickson DW: Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases, J Neuropathol Exp Neurol 2008, 67:649-656
5. Ko LW, Ko HH, Lin WL, Kulathingal JG, Yen SH: Aggregates assembled from overexpression of wild-type alpha-synuclein are not toxic to human neuronal cells, J Neuropathol Exp Neurol 2008, 67:1084-1096
6. Chartier-Harlin M-C, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, Hulihan MM, Kachergus J, Milnerwood AJ, Tapia L, Song M-S, Le Rhun E, Mutez E, Larvor L, Duflot A, Vanbesien-Mailliot C, Kreisler A, Ross OA, Nishioka K, Soto-Ortolaza AI, Cobb SA, Melrose, H. L., Behrouz B, Keeling BH, Bacon JA, Hentati E, Williams L, Yanagiya A, Sonenberg N, Lockhart PJ, Zubair AC, Uitti RJ, Aasly JO, Krygowska-Wajs A, Opala G, Wszolek ZK, Frigerio R, Maraganore DM, Gosal D, Lynch T, Hutchinson M, Bentivoglio AR, Valente EM, Nichols WC, Pankratz N, Foroud T, Gibson RA, Hentati F, Dickson DW, Destée A, Farrer MJ: Translation initiator EIF4G1 mutations in familial Parkinson’s disease, Am J Hum Genet 2011, in press
7. Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ: VPS35 Mutations in Parkinson Disease, Am J Hum Genet 2011, 89:162-167
8. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VM, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC: Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17, Proceedings of the National Academy of Sciences of the United States of America 1998, 95:13103-13107
9. Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM: Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease, Ann Neurol 2008, 64:88-92
10. Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, Aasly J, Annesi G, Bozi M, Brighina L, Chartier-Harlin MC, Destee A, Ferrarese C, Ferraris A, Gibson JM, Gispert S, Hadjigeorgiou GM, Jasinska-Myga B, Klein C, Kruger R, Lambert JC, Lohmann K, van de Loo S, Loriot MA, Lynch T, Mellick GD, Mutez E, Nilsson C, Opala G, Puschmann A, Quattrone A, Sharma M, Silburn PA, Stefanis L, Uitti RJ, Valente EM, Vilarino-Guell C, Wirdefeldt K, Wszolek ZK, Xiromerisiou G, Maraganore DM, Farrer MJ: Independent and joint effects of the MAPT and SNCA genes in Parkinson disease, Annals of neurology 2011, 69:778-792
11. Wider C, Vilarino-Guell C, Heckman MG, Jasinska-Myga B, Ortolaza-Soto AI, Diehl NN, Crook JE, Cobb SA, Bacon JA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, Wszolek ZK, Farrer MJ, Ross OA: SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study, Eur J Neurol 2010,
12. Nishioka K, Wider C, Vilarino-Guell C, Soto-Ortolaza AI, Lincoln SJ, Kachergus JM, Jasinska-Myga B, Ross OA, Rajput A, Robinson CA, Ferman TJ, Wszolek ZK, Dickson DW, Farrer MJ: Association of alpha-, beta-, and gamma-Synuclein with diffuse lewy body disease, Arch Neurol 2010, 67:970-975
13. Nishioka K, Ross OA, Ishii K, Kachergus JM, Ishiwata K, Kitagawa M, Kono S, Obi T, Mizoguchi K, Inoue Y, Imai H, Takanashi M, Mizuno Y, Farrer MJ, Hattori N: Expanding the clinical phenotype of SNCA duplication carriers, Mov Disord 2009, 24:1811-1819
14. Cobb SA, Wider C, Ross OA, Mata IF, Adler CH, Rajput A, Rajput AH, Wu RM, Hauser R, Josephs KA, Carr J, Gwinn K, Heckman MG, Aasly JO, Lynch T, Uitti RJ, Wszolek ZK, Kapatos G, Farrer MJ: GCH1 in early-onset Parkinson's disease, Mov Disord 2009, 24:2070-2075
15. Ross OA, Soto AI, Vilarino-Guell C, Heckman MG, Diehl NN, Hulihan MM, Aasly JO, Sando S, Gibson JM, Lynch T, Krygowska-Wajs A, Opala G, Barcikowska M, Czyzewski K, Uitti RJ, Wszolek ZK, Farrer MJ: Genetic variation of Omi/HtrA2 and Parkinson's disease, Parkinsonism & related disorders 2008, 14:539-543
16. Toft M, Haugarvoll K, Ross OA, Farrer MJ, Aasly JO: LRRK2 and Parkinson's disease in Norway, Acta neurologica Scandinavica 2007, 187:72-75
17. Farrer MJ, Stone JT, Lin CH, Dachsel JC, Hulihan MM, Haugarvoll K, Ross OA, Wu RM: Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia, Parkinsonism Relat Disord 2007, 13:89-92
18. Perez-Pastene C, Cobb SA, Diaz-Grez F, Hulihan MM, Miranda M, Venegas P, Godoy OT, Kachergus JM, Ross OA, Layson L, Farrer MJ, Segura-Aguilar J: Lrrk2 mutations in South America: A study of Chilean Parkinson's disease, Neurosci Lett 2007, 422:193-197
19. Papapetropoulos S, Farrer MJ, Stone JT, Milkovic NM, Ross OA, Calvo L, McQuorquodale D, Mash DC: Phenotypic associations of tau and ApoE in Parkinson's disease, Neuroscience letters 2007, 414:141-144
20. Haugarvoll K, Toft M, Ross OA, White LR, Aasly JO, Farrer MJ: Variants in the LRRK1 gene and susceptibility to Parkinson's disease in Norway, Neurosci Lett 2007, 416:299-301
21. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL, 3rd, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R: TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers, Neurology 2011, 76:467-474
22. Hsiung GY, Fok A, Feldman HH, Rademakers R, Mackenzie IR: rs5848 polymorphism and serum progranulin level, J Neurol Sci 2011, 300:28-32
23. Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL, 3rd, Ferrer I, Llado A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, Dekosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, DeCarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tunon MT, Martinez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM: Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions, Nature genetics 2010, 42:234-239
24. Carrasquillo MM, Nicholson AM, Finch N, Gibbs JR, Baker M, Rutherford NJ, Hunter TA, DeJesus-Hernandez M, Bisceglio GD, Mackenzie IR, Singleton A, Cookson MR, Crook JE, Dillman A, Hernandez D, Petersen RC, Graff-Radford NR, Younkin SG, Rademakers R: Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma, Am J Hum Genet 2010, 87:890-897
25. Gitcho MA, Bigio EH, Mishra M, Johnson N, Weintraub S, Mesulam M, Rademakers R, Chakraverty S, Cruchaga C, Morris JC, Goate AM, Cairns NJ: TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy, Acta Neuropathol 2009, 118:633-645
26. Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, Sorenson E, Lippa C, Bigio EH, Geschwind DH, Knopman DS, Mitsumoto H, Petersen RC, Cashman NR, Hutton M, Shaw CE, Boylan KB, Boeve B, Graff-Radford NR, Wszolek ZK, Caselli RJ, Dickson DW, Mackenzie IR, Petrucelli L, Rademakers R: Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis, PLoS Genet 2008, 4:e1000193
27. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, 3rd, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ: TDP-43 A315T mutation in familial motor neuron disease, Annals of neurology 2008, 63:535-538
28. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL, 3rd, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration, Hum Mol Genet 2006, 15:2988-3001
29. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17, Nature 2006, 442:916-919
30. Gijselinck I, Bogaerts V, Rademakers R, van der Zee J, Van Broeckhoven C, Cruts M: Visualization of MAPT inversion on stretched chromosomes of tau-negative frontotemporal dementia patients, Hum Mutat 2006, 27:1057-1059
31. Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, Baker M, Sleegers K, Crook R, De Pooter T, Bel Kacem S, Adamson J, Van den Bossche D, Van den Broeck M, Gass J, Corsmit E, De Rijk P, Thomas N, Engelborghs S, Heckman M, Litvan I, Crook J, De Deyn PP, Dickson D, Schellenberg GD, Van Broeckhoven C, Hutton ML: High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy, Hum Mol Genet 2005, 14:3281-3292
32. Rademakers R, Cruts M, van Broeckhoven C: The role of tau (MAPT) in frontotemporal dementia and related tauopathies, Hum Mutat 2004, 24:277-295
33. Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C: Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe, Hum Mutat 2003, 22:409-411
34. Hyman BT, Trojanowski JQ: Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease, J Neuropathol Exp Neurol 1997, 56:1095-1097
35. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M: Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium, Neurology 2005, 65:1863-1872
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37. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I: Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy), Neurology 1994, 44:2015-2019
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Public Health Statement

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.