Lewy body dementia, 𝛼-synuclein, and cell-specific mechanisms of neurodegeneration

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Grant Application Details

Application Title:

Lewy body dementia, 𝛼-synuclein, and cell-specific mechanisms of neurodegeneration

Public Abstract:
Research Objective

We will generate insights about mechanisms by which 𝛼-synuclein leads to neurodegeneration of the forebrain and substantia nigra, regions affected in Lewy body dementias and Parkinson disease.


If the proposed studies are successfully achieved, they will impact our understanding of Lewy body dementias specifically and 𝛼-synucleinopathies and neurodegeneration more broadly.

Major Proposed Activities

  • Differentiate iPSCs from affected, unaffected and gene-corrected individuals into forebrain and dopaminergic neurons.
  • Transduce neurons with biosensors to visualize biological pathways relevant to hypothesized mechanisms of neurodegeneration.
  • In some cultures, perform genetic perturbations designed to investigate the cause-or-effect relationships of differentially expressed genes discovered by scRNAseq analysis of these models.
  • Perform automated imaging and longitudinal single cell analysis to further characterize the temporal dynamics of putative mechanisms of neurodegeneration and to evaluate the effects of perturbations.
  • Analyze the images with computational tools including machine learning / deep learning / artificial intelligence to discover and quantify disease phenotypes and effects of perturbations.
Statement of Benefit to California:
As the largest state in the US, California is the most affected by Lewy body dementias and Parkinson disease, which inflict tremendous suffering and financial burden on patients and their families. Our project will benefit Californians by pioneering new discoveries that may lead to therapies to alleviate this suffering. This project will also and generate intellectual property for California and employ Californians. The PI has a track record of leveraging CIRM funding to attract federal funding.