Funded Studies
This grant builds upon the research from a prior grant: Regulation of Tau Protein by MicroRNA
Objective/Rationale:
Previous data support that small non-coding gene regulatory RNAs, known as microRNAs, are dysregulated in Parkinson’s disease (PD). However, the disease-relevance of these changes remains unknown. We hope to learn how altered microRNA activities may impact disease onset and progression and determine whether certain microRNAs may represent therapeutic targets for PD.
Project Description:
Our preliminary data point specifically to a potentially PD-relevant interaction between microRNA miR-181 and the gene encoding tau, a critical protein for proper neuronal function. We will determine the impacts of modulating miR-181 brain activity in a model of PD and assess whether any changes might be acting through tau-dependent biological pathways.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Recently published data indicate that miR-181 levels are increased in PD patient brains. Our studies, which could reveal the biological and clinical relevance of these changes, have the potential to further establish miR-181 as an important biomarker of disease and potential therapeutic target for PD.
Anticipated Outcome:
We anticipate that our studies will demonstrate that miR-181 modulates disease outcomes, including motor performance and brain pathology, in PD models. This will support new avenues of investigation to refine the mechanism of miR-181 action in PD and determine whether any effects can be validated in other models of PD. Furthermore, we expect that our work will spur additional studies querying the roles of other PD-relevant miRNAs in brain.
Final Outcome
In this study, we hypothesized that microRNAs -- molecules that can turn off genes and block production of proteins -- play a role in Parkinson's disease (PD). We aimed to test whether one particular microRNA, miR-181, can influence the disease-related outcomes in pre-clinical models with Parkinson's features. Firstly, we developed virus-based experimental tools called vectors to increase or decrease the production of miR-181 in the brains of the models. These vectors could either increase brain levels of miR-181 up to 8-fold or decrease them. Next, we produced and tested viral vectors to increase brain levels of alpha-synuclein, a sticky protein that clumps in the brains of people with PD. These vectors allowed us to create pre-clinical models with Parkinson's features such as severe neurodegeneration. Treating these models with miR-181-reducing vectors blocked neurodegeneration almost completely, while treating them with miR-181-increasing vectors aggravated it. We were unable to determine whether the miR-181-reducing vectors improved the behavior of pre-clinical models. These findings set the stage for future studies aimed at defining the mechanism of action of these neuroprotective vectors and evaluating their potential to treat Parkinson's disease in the clinics.