Alpha-synuclein Expression Lowering therapeutics: Hit Confirmation
MJFF Research Grant, 2011
Simply increasing dosage of the wild-type alpha-synuclein gene (SNCA) is sufficient to cause dopaminergic neurodegeneration and Parkinson’s disease in rare families carrying an inherited duplication or triplication of the gene. It is widely believed that SNCA overexpression may play a similar role in some forms of the common, sporadic disease. Brains of most patients with Parkinson’s are littered with intracellular accumulations of alpha-synuclein, a small 140 amino-acid protein. To rid brains of Parkinson’s patients of alpha-synuclein toxicity one can attempt to clear the protein from the brain, block its transformation into toxic species, or ameliorate the consequences of alpha-synuclein toxicity. We hypothesize, that the most direct and acute solution, however, would address the problem at its origin and simply turn off excessive SNCA transcription.
We have screened 1,126 compounds of which > 85% are FDA-approved drugs and a diverse set of natural products, vitamins, health supplements, and alkaloids and found a small subset of hits that lowered the abundance of endogenous SNCA transcripts (either by directly or indirectly by modulating regulatory pathways). We will now confirm, evaluate, and begin to mechanistically characterize these preliminary hits.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If successful, our novel and cause-directed approach will delineate compounds that turn off excessive expression of endogenous human SNCA.
Validated SNCA-expression-lowering hits will be useful as tools for dissecting and understanding the pathways that regulate the transcription of endogenous SNCA. Moreover, such confirmed hits can be optimized and advanced for evaluation in pre-clinical model studies and translation into clinical trials.
Head of the Neurogenomics Lab and the Parkinson Personalized Medicine Initiative at Harvard and Brigham and Women’s Hospital
Associate Professor of Neurology at Harvard Medical School
Location: Cambridge, Massachusetts, United States