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Analyzing Genetic Modifiers Using a CRISPR Activation/Inhibition GBA-PD Model

Study Rationale:
Clinical and genetic studies show that mutations in the GBA gene are risk factors for developing Parkinson’s disease (PD) and lead to an accumulation of glycolipids in the lysosome (cell’s garbage disposal) with potential deleterious effects. But the experience of PD varies greatly, even in patients carrying the same GBA mutation. It is unclear if rare causal PD genes or common risk genes act in combination with GBA to dysregulate cellular functions and impact the risk of developing PD.

We hypothesize that repression of GBA gene expression will lead to decreased lysosomal function in human dopamine neurons. We also believe this effect will be aggravated by the overexpression of the protein alpha-synuclein or misexpression of other genes.

Study Design:
Using novel gene-editing (CRISPR) technologies, we will modulate the expression of GBA and other genes in human dopamine neurons. These candidate genes have been identified through genetic studies of PD, and bioinformatic and literature review. We will test the impact of GBA and candidate gene dysregulation on lysosomal dysfunction and cell death. We will use cutting-edge “omics” technologies to understand interactions between GBA and candidate genes that might explain the risk and outcome of a GBA mutation on the development of PD.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our long-term goal is to understand the connection of reduced GBA function and the dysregulation of candidate genes to explain disease diversity, identify therapeutic targets and allow more personalized treatment. The results from this study will inform mechanistic studies of common and divergent dysregulation caused by or converging on GBA function.

Next Steps for Development:
We will investigate identified or validated candidate genes for their therapeutic potential in PD. Insights gained from our analysis may improve our ability to predict disease onset and severity in GBA carriers and expand therapeutic options.


  • Tim Ahfeldt, PhD

    New York, NY United States

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