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The Morris K. Udall Parkinson's Disease Research Center of Excellence at the Mayo Clinic is an integrated, multidisciplinary center that studies the Genetics and Molecular Biology of Parkinsonism. This Center draws upon the clinical strengths of the Mayo Clinic Movement Disorder Division, as well as epidemiologic and longitudinal studies of Parkinson's disease (PD), dementia with Lewy bodies and aging at Mayo Clinic.

The Clinical Core is an international effort to identify and characterize multiplex families with PD for genetic studies. Large kindreds with PD are collected and characterized in an effort to discover new genes for PD. Functional imaging studies are used to detect preclinical cases in these kindreds in order to increase the statistical power of the kindreds. Other initiatives are studies of the genetics of restless legs syndrome (RLS) and familial dystonia. In addition to familial PD, the Clinical Core also recruits and follows sporadic PD patients and arranges for postmortem studies. The Genetic Core provides genetic screening on families and also performs genome-wide linkage studies in the most informative kindreds. This effort includes screening for known PD genes, such as genes for parkin, α-synuclein and Lrrk2. The Neuropathology Core performs postmortem evaluations of PD and related disorders, including a large (>400) and growing collection of progressive supranuclear palsy (PSP) brains. The PSP collection is the largest in the world and DNA from this collection has contributed to identification of genetic risk factors for PSP. The Neuropathology Core also provides histologic support to the projects as well as DNA or brain tissue to researchers in the Mayo Clinic and other institutions. One of the major outcomes from this collaboration was the discovery of a new gene for frontotemporal dementia with Parkinsonism on chromosome 17, namely progranulin (PGRN). Clinicopathologic studies of these cases reveal parkinsonism in over 70% of the cases. The pathology in PGRN related FTDP is characterized by TDP-43 immunoreactive neuronal inclusions. Further work by the Neuropathology Core has identified TDP-43 immunoreactive inclusions in disorders other than frontotemporal dementia, including some cases of familial PD.

Project 1 builds upon the discovery, based upon research performed in the Udall Center, that there is multiplication of the α-synuclein gene (SNCA) in some cases of autosomal dominant, early-onset PD. This project focuses on population genetics of SNCA, characterization of SNCA multiplications (including the size and genes within the multiplication regions), and measurement of temporal and regional α-synuclein expression in normals and α-synucleinopathies. A recently published collaborative study with Global Genetics Consortium of Parkinson's disease, reported the first meta-analysis on over 2,500 PD cases and over 2,400 controls, which provided conclusive evidence that a polymorphism in SNCA is associated with risk of PD even in sporadic PD.

Project 2 is a clinicopathologic study that determines the frequency and clinical expression of Lewy bodies in normal individuals using the Mayo Medical Records Linkage System, with studies on the role of neuronal loss, inflammation and tau on clinical features. The goal is to identify preclinical PD and to evaluate epidemiologic risk factors in this cohort compared to controls that do not have Lewy bodies. A recent observation from this study provides evidence to suggest that spinal cord involvement occurs early in preclinical phase of PD. Analyses of striatal dopaminergic innervation indicates that striatal dopamine is decreased in preclinical PD compared to normals; however the decrease is less than in PD.

Project 3 uses cell lines that inducibly express α-synuclein or tau in conjunction with oxidative stress or mitochondrial toxins, such as rotenone, to study truncated and aggregated α-synuclein, with the goal of determining the role of interacting proteins in aggregate formation and the effects of aggregates on proteasome function and gene expression. Experimental evidence from these studies suggests that casein kinase 2 and G protein receptor kinase 2 are involved in α-synuclein phosphorylation and that α-synuclein proteolysis involves calpain and lysosomal enzymes, such as cathepsin D. Both phosphorylation and proteolysis play a role in α-synuclein aggregation and may prove to be key targets for disease modifying drug therapies for PD.

Discovery of a New Gene for Parkinson's Disease
The major discovery of the Udall Center, in collaboration with scientists in Germany and Austria, was finding the gene for autosomal dominant, late-onset PD linked to chromosome 12. The gene is called LRRK2, and is a large gene with 51 exons. The predicted 280-kDa protein has several functional domains, including a Roc domain that belongs to the Ras/GTPase superfamily, a COR domain, a leucine-rich repeat domain, a WD40 domain and a tyrosine kinase catalytic domain. The function of Lrrk2 and how disturbance in this function leads to PD remains to be determined, but preliminary results implicate its kinase function since several mutations have been found in this domain.

The discovery of LRRK2 was made possible through the efforts to the Clinical and Genetic Cores in identifying and characterizing large PD kindreds with autosomal dominant inheritance. In particular, two families (Family A and Family D) that were extensively characterized by the Clinical Core were found to carry different mutations in LRRK2. Screening of other familial PD cases by the Genetic Core identified several other families with distinct mutations. Given the results of studies in our Center and from others, it has become clear that mutations in LRRK2 are the most common genetic cause of autosomal dominant PD. The Genetic Core has assessed LRRK2 frequency, prevalence and penetrance estimates in incident, community-based and post-mortem samples from many ethnicities. Common, but distinct mutations in LRRK2 have been discovered in Caucasian and Asian populations that account for a sizable component to genetically-determined PD in both populations.

Pathologic characterization of six individuals from Families A and D who came to autopsy by the Neuropathology Core has shown mixed pathology. Three individuals had "nonspecific" neuronal loss and gliosis in the substantia nigra; two individuals had Lewy bodies (including one with diffuse Lewy body disease); and one had tau pathology, with neuronal and glial lesions that resembled those seen in 4R tauopathies, such as progressive supranuclear palsy. The Genetic Core has screened DNA samples of PD and other disorders from our brain bank and found additional cases with LRRK2 mutations. While most have had Lewy bodies, several have had either nonspecific pathology or tau pathology, as in the original studies of Families A and D. These studies have raised the possibility that disturbance in Lrrk2 may be "upstream" of a number of different pathologic processes that lead to neurodegeneration and suggest that treatments targeting Lrrk2 may have relevance not only to PD, but to other neurodegenerative disorders such as PSP and FTDP.

Publications

  1. Farrer MJ, et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism Relat Disord 2007;13:89-92.
  2. Fuchs J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 2007;68:916-22
  3. Melquist S, et al. Identification of a novel risk locus for progressive supranuclear palsy by a pooled genome wide scan of 500,288 single-nucleotide polymorphisms. Am J Hum Genet 2007;80:769-78.
  4. Amador-Ortiz C, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 2007;61:435-45.
  5. Maraganore DM, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661-70.
  6. Gass J, et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15:2988-3001.
  7. Klos KJ, et al. Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 2006;66:1100-2.
  8. Vega IE, et al. Taxol and tau overexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10. Exp Neurol 2006;202:152-60.
  9. Ross OA, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388-93.
  10. Zimprich A, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-7.

Last updated August 13, 2007