Funded Studies
Study Rationale:
Scientists can take skin cells from people with Parkinson’s disease (PD), turn them into stem cells, and then engineer them into dopamine neurons, the cell type lost in PD. Our laboratory recently used this model to identify the protein called histone deacetylase 4 (HDAC4) as a regulator of genes involved in PD. In patients carrying a mutation in the GBA gene, HDAC4 is misplaced in the nucleus, where it represses the expression of genes important for cellular function, resulting in PD-related pathology. When cells were treated with the HDAC4 inhibitor tasquinimod, we observed an increase in repressed gene expression and a reversal of PD-related pathology, identifying HDAC4 as a potential modifier of PD development.
Hypothesis:
We aim to validate HDAC4 as a novel therapeutic drug target by showing that inhibiting its function can alleviate the development of PD cellular pathology in stem cell-derived neurons from PD patients carrying mutations in the LRRK2, GBA or SNCA genes and in a PD model (SNCA-OVX).
Study Design:
First, we will observe the effect of PD mutations on HDAC4 misplacement in stem cell-derived neurons. We will then inhibit HDAC4 activity with tasquinimod and observe the effect on PD cellular pathology. In parallel, we will reduce the expression of HDAC4 to see if that also relieves PD cellular dysfunction. Next, we will investigate the effect of tasquinimod in an aged PD model and measure its effects on PD symptoms and PD gene expression changes specifically in dopamine neurons. Finally, we will look for HDAC4 misplacement in human brain tissue from control volunteers and PD patients.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We will identify whether the inhibition of HDAC4 by therapeutic intervention could help against the development of PD. Identifying HDAC4 as a novel therapeutic target could open avenues in PD prevention/treatment.
Next Steps for Development:
Inhibiting HDAC4 function in stem cell-derived neurons and in models will validate HDAC4 as a target, which will help our progress in designing better, more efficient drugs against HDAC4. This will give us valuable information to inform larger pre-clinical studies and ultimately work with human volunteers.