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Funded Studies

Alpha-Synuclein-Expression-Lowering Therapeutics: Initial Pre-Clinical Development

Increased dosage of the alpha-synuclein gene is linked to Parkinson’s disease (PD). Out of 1,126 FDA-approved compounds and health supplements screened, we identified a small number of preliminary hits that modulate the expression of endogenous neuronal alpha-synuclein micro RNA abundance in cultured neuroblastoma cells.

Project Description:             
Here we will pre-clinically develop these preliminary hits.

  • We will evaluate the effect of these hits specifically on endogenous alpha-synuclein protein.
  • We will delineate their in vivo pharmacokinetics and brain penetrance.
  • We will determine whether a prioritized hit lowers the expression of endogenous alpha-synuclein in the PD-vulnerable substantia nigra of pre-clinical models.
  • We will perform a counter screen to assess for off-target effects.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Compounds that lower endogenous alpha-synuclein expression will be useful probes for dissecting the pathobiology of Parkinson’s and may serve as stepping stones for novel therapeutics.

Anticipated Outcome:          
Our novel and cause-directed approach may delineate compounds that lower expression of endogenous human alpha-synuclein in pre-clinical models.

Final Outcome

This study highlighted a class of alpha-synuclein (SNCA) expression-lowering chemicals in human neuroblastoma cells, primary cortical neurons, as well as in pharmacokinetic and efficacy trials in pre-clinical models. Moreover, by correlating systems pharmacology, gene silencing, endogenous gene and protein expression with quantitative chromatin immunoprecipitation analyses, we delineated a druggable, receptor-mediated pathway regulating the transcription of endogenous SNCA. 


  • Clemens Scherzer, MD

    Boston, MA United States

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