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.
November 2020 Project Update:
Over the course of this year, we investigated the relationship between alpha-synuclein and mRNA biology in neurons in multiple ways. Our focus is on P-bodies, structures in the cell that play a fundamental role in mRNA storage and decay. By using induced pluripotent stem cell (IPSC) lines created from people with specific alpha-synuclein mutations, we were able to show that alpha-synuclein not only interacts with, but also changes the internal composition of P-bodies in human neurons. We are currently investigating these interactions in post-mortem brains of people with PD. Our findings help to explain the relationship between alpha-synuclein and impaired mRNA biology, with the ultimate aim of creating gene therapies that manipulate mRNAs to function properly in the context of PD.
October 2021 Project Update:
Over the course of the last two years, we investigated the relationship between alpha-synuclein and mRNA biology in neurons in multiple ways. Our focus is on P-bodies, structures in the cell that play a fundamental role in mRNA storage and decay. By using induced pluripotent stem cell (IPSC) lines created from people with specific alpha-synuclein mutations, we were able to show that alpha-synuclein not only interacts with, but also changes the internal composition of P-bodies in human neurons.
In this last year, we have made some exciting progress. We have shown that what we identified in stem-cell derived brain cell from patients also occurs within the postmortem brains of patients. Moreover, we see strongly suggestive indications in human genetic analysis that this pathway is important in contributing to PD risk.
Our findings help to explain the relationship between alpha-synuclein and impaired mRNA biology, with the ultimate aim of creating gene therapies that manipulate mRNAs to function properly in the context of PD.
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