Project 2: Genetic determinants of alpha-synuclein and tau pathology in parkinsonism

  • Image showing alpha-synuclein protein positive inclusions (Lewy bodies)

    Immunohistochemistry showing the presence of alpha-synuclein protein positive inclusions (Lewy bodies) that characterize the brains of patients with Parkinson's disease.

Immunohistochemistry showing the presence of alpha-synuclein protein positive inclusions (Lewy bodies) that characterize the brains of patients with Parkinson's disease.

This project uses intermediate pathological phenotypes to explore associations with genetic variants in progressive supranuclear palsy (PSP) and Lewy body dementia (LBD). The results will provide insights into the molecular underpinnings of parkinsonian disorders. Researchers are using microtubule-associated protein tau (MAPT), as well as non-MAPT single nucleotide polymorphisms (SNPs), from genome-wide association studies.

The specific aims are to:

  1. Generate intermediate pathological phenotypes for PSP. Measurements of burden of tau are obtained with digital microscopy from PSP brains for which clinical, biochemical and neuropathological phenotypes are collected.
  2. Assess association of intermediate pathological phenotypes with gene variants in PSP. Genetic variants from the PSP genome-wide association studies are tested for association against neuropathological, biochemical and clinical phenotypes with the goal of identifying mechanisms of genetic risk variants in PSP.
  3. Generate intermediate pathological phenotypes for Lewy body dementia. Measurements of burden of alpha-synuclein, amyloid beta and tau with digital microscopy in LBD brains are obtained for which clinical and pathological phenotypes are collected.
  4. Assess association of intermediate pathological phenotypes with gene variants from PD. Genetic variants from autopsy PD genome-wide association studies, as well as two MAPT variants, are tested for association with clinical and pathological phenotypes.

Ultimately, genetic and phenotypic data on a large number of progressive supranuclear palsy and Lewy body dementia brains not only provide mechanistic insight but also are a resource for Udall Center collaborators and others.