Investigator:
Emily Rocha, MD, PhD
Name of Institution:
University of Pittsburgh
Project Title:
Lysosomal dysfunction in Parkinson’s disease
Investigator Bio:
Dr. Rocha is an Assistant Professor at the Pittsburgh Institute for Neurodegenerative Diseases (PIND) and the Department of Neurology at the University of Pittsburgh. Dr. Rocha is interested in the intersection between lysosomes and aging and how it impacts the onset of age-related neurodegenerative diseases, like Parkinson’s disease (PD).
Dr. Rocha received her PhD from Carleton University, Ottawa Canada. From there, she completed her first post-doctoral fellowship at Harvard Medical School under the mentorship of Dr. Ole Isacson, MD. She then moved to the University of Pittsburgh to complete her post-doctoral studies under the mentorship of Tim Greenamyre, MD-PhD. As a post-doctoral fellow, Dr. Rocha focused on lysosomal biology and the role of the lysosomal enzyme glucocerebrosidase in alpha-synuclein (a-syn) accumulation in PD.
As an Assistant Professor, Dr. Rocha is focused on identifying and validating new therapeutic strategies to improve lysosomal function in dopamine neurons. She applies a multidisciplinary approach incorporating genetic, molecular, and cellular-based techniques in cell lines, primary neurons, and rodents to understand the mechanism(s) responsible for age-related endolysosomal dysfunction and to dissect molecular mechanisms that cause lysosomal deficits and contribute to neuronal dysfunction and eventual neurodegeneration in models of PD. She also tests novel therapeutic targets in preclinical models of PD to determine whether they could be disease-modifying candidates.
Objective:
To assess whether TRPML1 could be a disease modifying therapy to slow neurodegeneration in PD.
Background:
Accumulation of aggregated proteins is a pathological hallmark of PD. We and others hypothesize that dysfunctional lysosomes may be central to the pathophysiology of PD.
TRPML1 belongs to the Transient Receptor Potential (TRP) multigene superfamily that transports positively charged molecules such as calcium from inside the lysosome to the rest of the cell. Lysosomal calcium release can activate Transcription factor EB (TFEB), which regulates lysosomal function in many ways including stimulating the creation of new lysosomes. Since TFEB promotes lysosomal health, it is not surprising that overexpressing TFEB and inducing TFEB activity is neuroprotective in animal models of neurodegeneration, including PD. Therefore, targeting TRPML1 could be a disease modifying strategy to improve lysosomal health and halt the progression of PD.
Methods/Design:
This project will evaluate the therapeutic relevance of targeting TRPML1 for PD. In collaboration with the University of Pittsburgh neuropathology department, postmortem PD and age-matched control brain tissue will be used to assess whether TRPML1 in dopamine neurons, astrocytes, and microglia is changed in comparison to age-matched control brain tissue. We will also use a rat model of PD to assess whether overexpression of TRPML1 using a gene therapy approach is neuroprotective.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project focuses on whether stimulating a specific lysosomal cation channel, TRPML1, could improve lysosomal health and slow ongoing dopaminergic neurodegeneration. Pharmaceutical companies are already developing small molecule TRPML1 agonists, and our work will be an initial proof-of-concept, to explore whether this approach may be beneficial in a rat model of PD.