Project 2 will use intemnediate pathologic phenotypes to explore associations with genetic variants in progres- sive supranuclear palsy (PSP) and Lewy body disease (LBD). The results will provide insights into the molecular underpinnings of Parkinsonian disorders. We will use MAPT, as well as non-M(4PT single nucleotide polymor- phisms (SNPs) from genome-wide association studies (GWAS).
Aim 1. Generate intermediate pathologic phenotypes for PSP. We will measure burden of tau using digital imaging in superior frontal gyrus, motor cortex, amygdala, caudate nucleus, pontine base and cerebellar dentate nucleus;microgliosis with IBA-1 immunohisto- chemistry in subthalamic nucleus and substantia nigra. We will record clinical phenotypes (sex, diagnosis, age at onset, age at death, disease duration), pathologic groupings (typical PSP vs. atypical PSP;pure PSP vs. mixed PSP), semi-quantitative scores of neuronal, astrocytic and oligodendroglial lesion density, biochemical characte- rization of tau from Western blots of caudate nucleus, and estimated latent trait variables constructed from the semiquantitative lesion scores.
Aim 2. Assess association of intermediate pathologic phenotypes with gene variants in PSP. We will focus on 2 AMPT SNPs and 23 non-MAPT SNPs that achieved p<1x10'^ in the PSP GWAS. Each SNP will be tested for association in more than 700 PSP cases against 5 primary pathologic phe- notypes. We hypothesize that intermediate pathologic phenotypes, a large sample size and targeted SNPs will be powerful in identifying mechanisms of genetic risk variants in PSP.
Aim 3. Generate intermediate patholog- ic phenotypes for LBD. We will measure burden of a-synuclein, A3, and tau in mid-frontal gyrus, superior tem- poral gyrus, amygdala and putamen;tyrosine hydroxylase immunohistochemistry of putamen;and microgliosis in substantia nigra and basal nucleus of Meynert. We will record clinical phenotypes (as for PSP, but also dementia and/or Parkinsonism), pathological phenotypes (brainstem, transitional, or diffuse LBD;pure LBD vs. mixed LBD) as well as Lewy body counts in 5 cortical areas and the amygdala. We will estimate latent trait variables underly- ing the semiquantitative scores of LBs, plaques and tangles as in Aim 1.
Aim 4. Assess association of inter- mediate pathologic phenotypes with gene variants from PD GWAS. SNPs will be identified as top hits from the autopsy PD GWAS. We will focus on 2 MAPT SNPS and 23 non-/W>! P7SNPs that achieved p<1x10'(R). Each SNP will be tested for association with 9 intermediate phenotypes in more than 700 LBD cases. Ultimately, ge- netic and phenotypic data on a large number of PSP and LBD brains will not only provide mechanistic insight, but also be a resource for Udall Center collaborators and for others.

Public Health Relevance

(See Instmctions): The research proposed in this project will collect detailed pathologic and molecular information on a large number of brains from individuals who died with either Parkinson's disease (PD) or progressive supranuc- lear palsy (PSP). This information will be to detailed genetic information collected on the same brain to de- termine which genes are responsible for the pathologic changes found in these brains. These studies will lead to a better understanding of the genes involved in PD and PSP.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-J (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic Jacksonville
United States
Zip Code
Lorenzo-Betancor, Oswaldo; Wszolek, Zbigniew K; Ross, Owen A (2016) Rare variants in MC1R/TUBB3 exon 1 are not associated with Parkinson's disease. Ann Neurol 79:331
Kovacs, Gabor G; Ferrer, Isidro; Grinberg, Lea T et al. (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 131:87-102
Tacik, Pawel; Sanchez-Contreras, Monica; Rademakers, Rosa et al. (2016) Genetic Disorders with Tau Pathology: A Review of the Literature and Report of Two Patients with Tauopathy and Positive Family Histories. Neurodegener Dis 16:12-21
Tipton, Philip W; Konno, Takuya; Broderick, Daniel F et al. (2016) Cerebral peduncle angle: Unreliable in differentiating progressive supranuclear palsy from other neurodegenerative diseases. Parkinsonism Relat Disord 32:31-35
Williams, Kelly L; Topp, Simon; Yang, Shu et al. (2016) CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun 7:11253
Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya et al. (2016) Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review. Neuropathology 36:64-76
Tacik, Pawel; Curry, Sadie; Fujioka, Shinsuke et al. (2016) Cancer in Parkinson's disease. Parkinsonism Relat Disord 31:28-33
Jiang, Peizhou; Gan, Ming; Yen, Shu-Hui et al. (2016) Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons. Acta Neuropathol 132:77-91
Soto-Ortolaza, Alexandra I; Ross, Owen A (2016) Genetic susceptibility variants in parkinsonism. Parkinsonism Relat Disord 22 Suppl 1:S7-11
Walton, Ronald L; Soto-Ortolaza, Alexandra I; Murray, Melissa E et al. (2016) TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet 2:e85

Showing the most recent 10 out of 218 publications