Unity Walk > American Parkinson Disease Research Grants 2019

 

American Parkinson Disease Association is using its 2019 distribution to fund:

Investigating RIPK3 as a driver of inflammatory astrocyte activation in Parkinson’s disease

Molecular mechanisms of perturbed mRNA metabolism in alpha-synucleinopathy

 

PROJECT TITLE:  Investigating RIPK3 as a driver of inflammatory astrocyte activation in Parkinson’s disease

Investigator/Author:  Brian Daniels, PhD

Objective:  Our study will investigate the role of the protein RIPK3 in the inflammatory response in the brains of people with Parkinson’s disease. 

Background:  Inflammation in the brain plays an important role in the pathologic changes of PD. Astrocytes, a cell type in the brain with a variety of functions, can become activated during the neurodegeneration of PD and promote inflammation. Recent work has also shown that a group of proteins called Receptor Interacting Protein Kinases (RIPKs) are key players in promoting inflammation in a variety of neurodegenerative conditions, and inhibitors of RIPKs are currently in clinical trials for both Alzheimer’s disease and Amyotrophic lateral sclerosis. Increased RIPK activity has been observed in PD as well, but its role is not fully understood.  This study will investigate the specific role of RIPK3 signaling in the development of neuroinflammation in PD.

Methods/Design:  Dr. Daniels will utilize several genetic systems to change RIPK3 signaling in astrocytes, both in a cell culture model and a mouse model of PD. For the mouse studies, he will use a well-established model in which mice are administered a neurotoxin that selectively kills dopamine neurons in the midbrain. He will then assess how astrocytes respond to inflammation as RIPK3 is being artificially suppressed or increased.

Relevance to Diagnosis/Treatment of Parkinson’s Disease: If we understand the processes by which RIPKs contribute to inflammation in PD, inhibitors of RIPK, which are already in clinical development, can be tried as new PD therapies.

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PROJECT TITLE:  Molecular mechanisms of perturbed mRNA metabolism in alpha-synucleinopathy

Investigators/Authors:  Vikram Khurana, MD, PhD

Objectives: Our study will investigate the dysregulation of messenger RNA (mRNA) in Parkinson’s disease (PD)

Background: In past work, Dr. Khurana studied the interactions of α -synuclein, the protein that accumulates in the brains of people with Parkinson’s disease, in living cells. He surprisingly discovered that α -synuclein interacts with messenger ribonucleic acids (mRNAs), which are the intermediary molecules between DNA and the proteins that they encode. In this project, he delves into this interaction, studying the exact role of mRNA dysfunction in PD neurons.

Methods/Design: Dr. Khurana has created a series of induced pluripotent stem cell (IPSCs) lines, which are stem cells created from adult tissue. The cell lines are generated from people with specific mutations in α -synuclein or over-expression of α -synuclein. Dr. Khurana then differentiates these stem cells into dopamine neurons and studies the effects that the α -synuclein mutations have on the biology of the cells. Dr. Khurana will use these cells to investigate the changes in mRNA biology that can be attributed to α -synuclein mutations.

Relevance to Diagnosis/Treatment of PD: By understanding how PD changes mRNA functioning, gene therapy treatments can be developed that manipulate the RNA biology to function properly.

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