Director: Dennis W. Dickson, M.D.
Title: Genetics and Molecular Biology of Parkinsonism
Budget End Date: 6/30/2017
The Udall Center Mayo Clinic in Jacksonville, Florida, is an integrated, multi-disciplinary research program on the “Genetics and Molecular Biology of Parkinsonism.” The major focus of the research is on two molecular forms of Parkinsonism, namely parkinsonism associated with α-synuclein pathology [Parkinson’s disease (PD, Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB)) and multiple system atrophy (MSA)] as well as parkinsonism associated with tau pathology [progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)].
The Mayo Clinic Udall Center draws upon strengths of clinical genetics of familial parkinsonian disorders conducted by the Clinical Core and on the growing collection of parkinsonian brains collected by the Neuropathology Core. The Genetic Core is tightly linked to the other cores and to the two funded projects. Research projects are focused on gene discovery for parkinsonian disorders (Project 1) and on the pathologic correlates of common genetic variants identified through genome wide association studies of PSP and PD (Project 2).
Project 1 conducted a genome-wide sequencing study of a large family with pathologically confirmed CBD in the proband and has identified novel genetic variants on 4 genes that were present in both patients from the family and not in 750 control individuals. These genes are SCN10A, OPRK1, CAPRIN2 and UBN1. To obtain additional evidence for pathogenicity for these genes, the functional domains were sequenced in 145 pathology-confirmed CBD cases.
Whole genome sequencing in three pathologically confirmed PSP sib-pairs identified a novel MAPT mutation in one pair, but not in the other two sib-pairs. Whole genome sequencing was analyzed through two different bioinformatics pipelines (Radboud University Medical Center Nijmegen and the Ingenuity Variant Analysis software). In each sib-pair 54 variants were identified by at least one of the pipelines and they were chosen for validation with Sequenom iPLEX analyses in 1062 controls. Additionally, the Sequenom panels were used to screen 1026 and 145 pathology-confirmed PSP and CBD cases, respectively, with the aim of detecting unrelated mutation carriers. Three PSP cases and one CBD case carried four of the variants (HTRA2, GCFC2, ASB14 and PLEKHG3) which were assigned as high priority given the rarity of these variants and the low chance of finding the same variant in unrelated individuals. Bioinformatics tools were used to detect potential interactions and pathways between the 54 variants. Using STRING, an online database of known and predicted protein interactions, a main network was identified in which one node linked HTRA2, AATF, and FBL. Each one of these three proteins is mutated in one of the families. This analysis also showed that this interaction node is associated with tau. Using three additional online pathway analysis tools to identify functional-related gene groups, an additional functional group was identified: HTRA2 and mitochondrial complex I deficiency (NDUFA10 and NDUFA11), both of them involved in the Parkinson’s disease.
In Project 2 findings from the first GWAS of CBD indicate that PSP and CBD may share genetic risk factors other than MAPT. A locus of chromosome 3 is of particular interest as it contains two promising candidate genes – myelin oligodendrocyte basic protein and apoptosin. Genetic studies by Project 2 have identified correlates with Lewy related pathology. To explore genetic associations with pathologic variables for Lewy-related parkinsonism, Core C genotyped 547 cases of autopsy-confirmed Lewy body disease from Mayo Clinic for which Lewy body counts as well as information on Alzheimer type pathology were available. Individuals who were carriers of known mutations in PD gene were excluded. Demographic and neuropathological information was collected regarding age at death, gender, severity of Lewy body pathology (brainstem LBD, transitional LBD, or diffuse LBD), Braak stage, likelihood of clinical dementia with Lewy bodies (DLB) according to both the original and modified CLBD criteria, brain weight, Lewy body count in the cingulate gyrus, inferior parietal, mid frontal, parahippocampal, and superior temporal regions, and total Lewy body count across all 5 brain regions. Total Lewy body count was calculated for the 5 brain regions. Core C genotyped 42 different SNPs that have been nominated as risk factors for PD. Nominally significant associations for burden of Lewy body pathology were observed for variants in or near the BST1, LRRK2, BCKDK/STX1B, MAPT, FGF20, SNCA, and SPPL2B genes. Given that many of the cases had DLB rather than PD as the primary clinical diagnosis, we compared pathologic associations for those SNPs shared between our analysis and those in the recently reported DLB GWAS (PMCID: PMC4222357); the Mayo Clinic Udall Center was the major contributor of autopsy-confirmed DLB to that multicenter study. Several of the top hits in the DLB GWAS were also associated with Lewy body counts in the Mayo association study (BCKDK/STX1B OR 1.09, p=0.011; LRRK2 OR 0.82, p=0.06, SNCA OR 1.17, p=0.06). These results suggest that genetic variants shared between DLB and PD are linked to α-synuclein pathology and not Alzheimer type pathology. APOE was not a top association in our study; we are currently exploring the role of APOE with autopsy-confirmed and clinically-diagnosed DLB.
Center Goals aligned with NINDS PD2014 Research Priorities
Projects 1 and 2 address the following NINDS PD2014 Research Priorities:
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
Plans for the Coming Year
Project 1 will continue to search for novel tauopathy and α-synucleinopathy genes using next-generation sequencing approaches. Project 1 will also continue efforts towards gene identification in the families and sib-pairs already sequenced, focusing on analysis of HTRA2, the novel tauopathy gene nominated through the analysis of the sib-pairs. mRNA and protein expression studies will be performed three PSP patients carrying potential pathogenic variant (one sib-pair and one unrelated PSP patient). Each patient will be matched to two PSP patients without mutations and two controls and both motor cortex (affected) and occipital cortex (unaffected) regions will be studied.
This project will also further refine the list of candidate genes/variants within families with α-synucleinopathy and employ different avenues to investigate functional relevance and putative pathogenicity for variants of interest. Population-based studies (both genotype and sequence-based) will be exploited to prioritize genes and genomic loci of interest. Finally, 2.5 M SNP chip data on PSP sib-pairs and other tauopathies and α- synucleinopathy families will be analyzed for presence of copy-number mutations.
Project 2 will finish association studies of pathologic latent trait variables and genetic variants from the PSP GWAS, as well as report on application of latent variables for probing for association with genetic variants. Results of correlates with Lewy related pathology and top PD associated SNPs will be validated in additional cases. Association of APOE with clinical and pathologic variables in autopsy confirmed DLB will be explored.
Konno T, Ross OA, Puschmann A, Dickson DW, Wszolek ZK. Autosomal dominant Parkinson's disease caused by SNCA duplications. Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S1-6.PMID:26350119
Ogaki K, Koga S, Heckman MG, Fiesel FC, Ando M, Labbé C, Lorenzo-Betancor O, Moussaud-Lamodière EL, Soto-Ortolaza AI, Walton RL, Strongosky AJ, Uitti RJ, McCarthy A, Lynch T, Siuda J, Opala G, Rudzinska M, Krygowska-Wajs A, Barcikowska M, Czyzewski K, Puschmann A, Nishioka K, Funayama M, Hattori N, Parisi JE, Petersen RC, Graff-Radford NR, Boeve BF, Springer W, Wszolek ZK, Dickson DW, Ross OA. Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders. Neurology. 2015 Dec 8;85(23):2016-25. PMCID: PMC4676755 [Available on 2016-12-08].
Labbé C, Ogaki K, Lorenzo-Betancor O, Soto-Ortolaza AI, Walton RL, Rayaprolu S, Fujioka S, Murray ME, Heckman MG, Puschmann A, McCarthy A, Lynch T, Siuda J, Opala G, Rudzinska M, Krygowska-Wajs A, Barcikowska M, Czyzewski K, Sanotsky Y, Rektorová I, McLean PJ, Rademakers R, Ertekin-Taner N, Hassan A, Ahlskog JE, Boeve BF, Petersen RC, Maraganore DM, Adler CH, Ferman TJ, Parisi JE, Graff-Radford NR, Uitti RJ, Wszolek ZK, Dickson DW, Ross OA. Role for the microtubule-associated protein tau variants p.A152T in risk of α-synucleinopathies.Neurology. 2015 Nov 10;85(19):1680-6. PMCID: PMC4653108 [Available on 2016-11-10]
Lorenzo-Betancor O, Ogaki K, Soto-Ortolaza AI, Labbe C, Walton RL, Strongosky AJ, van Gerpen JA, Uitti RJ, McLean PJ, Springer W, Siuda J, Opala G, Krygowska-Wajs A, Barcikowska M, Czyzewski K, McCarthy A, Lynch T, Puschmann A, Rektorova I, Sanotsky Y, Vilariño-Güell C, Farrer MJ, Ferman TJ, Boeve BF, Petersen RC, Parisi JE, Graff-Radford NR, Dickson DW, Wszolek ZK, Ross OA. DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients. Eur J Neurol. 2015;22:1323-5. PMCID: PMC4542017 [Available on 2016-09-01]
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 Modified February 8, 2016