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/

Central Theme and Center Structure

The Udall Center of Excellence in Parkinson Disease’s Research at the Mayo Clinic is an integrated, multi-disciplinary research program that brings together neurologists, neuropsychologists, geneticists, neuropathologists and basic scientists in the study of the “Genetics and Molecular Biology of Parkinsonism.” The Udall Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Section as well as epidemiologic and longitudinal studies of Parkinson disease (PD) and longitudinal studies of dementia with Lewy bodies (DLB). These clinical studies provide data and biologic material used in the research projects. Mayo Clinic has a strong institutional commitment to PD research in the form of 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 intra-institutional collaborations.

The overarching goals of the Udall Center are to identify genes for PD through identification of families in which there are multiple affected individuals in more than one generation. Neuropathologic characterization of affected individuals that come to autopsy define the molecular pathology of the disease process. DNA from affected and unaffected individuals is analyzed by genome wide linkage analysis and genomic sequencing to identify causative genes. Once the gene is discovered, common and rare variants in the gene are studied as possible risk factors for sporadic PD. The gene is expressed in cell culture and animal models to better understand pathogenesis and to develop disease-modifying therapies.

 

Recent Significant Advances

Familial early onset PD and multiplication mutations in the gene for α-synuclein (SNCA)

The Mayo Clinic Movement Disorder section and the Clinic Core identified a family (Iowa kindred) that had a classic Mendelian pattern of inheritance of PD, with atypical features, including early dementia. Linkage studies demonstrated that these families were associated with a locus on chromosome 4. Neuropathologic studies demonstrated that affected individuals who came to autopsy had Lewy bodies, including cortical Lewy bodies typical of dementia with Lewy bodies. Cytogenetic studies and sequencing efforts lead to discovery of multiplication in SNCA. Other PD families were screened for SNCA multiplications, and several families were discovered, including the “Lister family complex” in Sweden, one of the largest pedigrees with familial PD first described by Lundborg in 1913. The Genetic Core established ties with neurologists at the University of Lund to identify further living branches of this pedigree in Sweden in order to characterize the natural history of disease and to study peripheral biomarkers, including α-synuclein levels in leukocytes and CSF.

Common genetic variability within SNCA was identified by linkage-disequilibrium and haplotype studies in several populations, including Belgian and Norwegian series. In both populations promoter variability was a risk factor for PD. These studies were extended in a Global Genetic Consortium of Parkinson disease (GEO-PD). A mixed dinucleotide repeat 9.8 Kb upstream of the SNCA transcriptional start site was analyzed in a large collection of PD and control DNA samples, and the results confirmed that genetic variants in SNCA confer risk for PD.

Leucine rich repeat kinase 2 mutations (LRRK2) in familial and sporadic PD

The Clinic Core identified several families (Families A and D) that had a classic Mendelian pattern of inheritance of PD. Linkage studies demonstrated that these families were associated with a locus on chromosome 12 (PARK8). Neuropathologic studies demonstrated that most of the affected individuals who came to autopsy had Lewy bodies, but several had tau pathology or nonspecific substantia nigra degeneration. Sequencing efforts lead to discovery of mutations in LRRK2. With this knowledge, other PD families were screened for LRRK2 mutations, and several families were discovered. Soon genetic studies with collaborators from around the world made it clear that this was the most common genetic cause of PD and that the clinical phenotype in most cases was very similar to typical late-onset sporadic PD. Sequencing of LRRK2 in different populations revealed not only causative mutations, but also genetic variants in LRRK2 that had strong association with risk for PD, particularly in Asian populations. A host of basic research studies on PD, including immunohistological, biochemical, molecular biology and cell biological studies, followed discovery of LRRK2 mutations in PD. Transgenic animal models were developed and are being studied in the hopes that they recapitulate features seen in PD.

Perry syndrome and mutations in dynactin p150

Perry syndrome is a rare and malignant, autosomal dominant, early onset parkinsonism associated with central hypoventilation and depression. Studies by the Clinical Core and collaborators in England, France, Japan and Canada as well as in West Virginia identified a number of kindreds with a similar clinical phenotype. Review of the neuropathology, with immunohistochemical approaches, revealed distinctive pathology not seen in previous studies, with TAR DNA binding protein of 43 kDa (TDP-43) immunoreactive inclusions in midbrain and basal ganglia. TDP-43 pathology is of interest as it is a link to frontotemporal lobar degenerations and amyotrophic lateral sclerosis. TDP-is also detected in a subset of Alzheimer and Lewy body disorders.

Genome wide linkage analysis of the most informative families by the Genetic Core lead to a linkage region on chromosome 2p13, and sequencing of genes in this region lead to discovery of mutations in the gene for dynactin p150 (DCTN1). Immunohistochemistry of Perry cases showed colocalization of components of the dynactin complex (p50) with TDP-43 inclusions. Cell biologic studies of wild type and mutant dynactin p150 are in progress. This discovery sheds new insights into the selective vulnerability of the substantia nigra and globus pallidus to neurodegenerative disorders and emphasizes the link of PD with amyotrophic lateral sclerosis and frontal lobe degenerations.

 

Available Resources

Brain and tissue bank

Human	Paraffin blocks	Stained slides	Fixed tissue	Frozen tissue
Lewy body disease	703	795	734	714
PSP	657	679	673	642
CBD	86	98	93	86
MSA	57	61	61	51
Mouse
Synuclein transgenic & controls	301
LRRK transgenic & controls	81

DNA samples

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

Mouse models

• 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

SNCA mutations and variants in familial and sporadic PD
Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, et al. Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 2004;55:174-179

Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661-670

LRRK2 mutation and variants in familial and sporadic PD
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-607

Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388-393

Dachsel JC, Taylor JP, Mok SS, Ross OA, Hinkle KM, Bailey RM, et al. Identification of potential protein interactors of Lrrk2. Parkinsonism Relat Disord 2007;13:382-385

Farrer MJ, Stone JT, Lin CH, Dachsel JC, Hulihan MM, Haugarvoll K, et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 2007;13:89-92

Perry syndrome, TDP-43 and mutations in DCTN1
Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, et al. Pallidonigral TDP-43 pathology in Perry syndrome. Parkinsonism Relat Disord 2009;15:281-6.

Farrer MJ, Hulihan MM, Kachergus JM, Dächsel JC, Stoessl AJ, Grantier LL, et al.. DCTN1 mutations in Perry syndrome. Nat Genet 2009;41:163-5.

 

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.