RNA regulation in medium spiny neurons of the striatum in Parkinson's disease

Rockefeller University, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Research: Parkinson's disease is characterized by degeneration of dopaminergic neurons in the substantia nigra, leading to reduced dopaminergic input to the striatum and subsequent motor and cognitive deficits. While the loss of presynaptic dopamine input initiates striatal dysfunction, mere replacement of dopamine is insufficient to effectively treat the disease over time. This gap in knowledge has spurred interest in understanding the molecular dysfunction within the postsynaptic neurons of the striatum. D1 and D2 neurons, named for their predominant expression of dopamine receptors D1 and D2, are the principal postsynaptic neurons of the striatum. They exhibit distinct downstream signaling mechanisms in opposing pathways that together influence striatal function. The overall objective of this project is to identify the molecular mechanisms underlying striatal dysfunction in Parkinson’s disease by investigating aberrant glutamate and dopamine receptor signaling separately in D1 and D2 postsynaptic neurons. This study focuses on the cell-type specific role of the neuronal RNA-binding protein ELAVL3, whose levels are altered in Parkinson’s disease. ELAVL3 is a known modulator of alternative splicing of mRNAs encoding proteins critical for glutamate and dopamine receptor signaling in the mouse striatum. The central hypothesis is that altered RNA-binding function of ELAVL3 leads to aberrant splicing in D1 and D2 neurons, ultimately disrupting striatal function in Parkinson’s disease. The applicant will test this hypothesis by leveraging technical breakthroughs in her mentors’ laboratories that enable the isolation of D1 and D2 neurons from postmortem brains to study RNA regulatory mechanisms within specific cell types. The project has two specific aims: 1) To identify the role of alternative splicing in aberrant glutamate and dopamine receptor signaling in Parkinson’s disease 2) To determine the role of ELAVL3 on alternative splicing and downstream signaling in D1 and D2 neurons in Parkinson’s disease. This research is expected to shed light on the molecular mechanisms involved in striatal dysfunction in Parkinson’s disease, potentially leading to the development of novel therapeutic approaches. Candidate: The applicant Dr. Krithi Irmady is a movement-disorders neurologist and Instructor at the Rockefeller University, who aims to become an independent, tenure-track physician- scientist investigating RNA biology in Parkinson’s disease. Dr. Irmady has outlined a five-year period of mentored training where she will develop skills in fluorescence activated nuclear sorting, cell-type specific profiling of RNA binding protein targets, and experimental manipulation of splicing in neuronal culture systems to study RNA dysregulation in Parkinson’s disease. Environment: The proposed research will be done in Rockefeller University, one of the world’s leading biomedical research universities. The University exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent investigators.