Huntington's disease (HD) is a fatal, genetic neurodegenerative disease that shares many features with other common neurological disorders. HD is caused by expansion of CAG repeats in exon 1 of the huntingtin gene, which leads to expression of mutant huntingtin (mHTT) protein with an extended polyglutamine (polyQ) tract. mHTT induces neuronal dysfunction, prominent striatal atrophy, and ultimately, cell death. A disease-modifying treatment for HD does not currently exist despite decades of study and numerous clinical trials, motivating the need for discovery of new therapeutic targets. One potential target is the RNA binding motif protein 3 (RBM3), a stress-response protein that enhances synaptogenesis, protein translation, and cell survival. RBM3 is reduced in neuronal cell models of HD, and my preliminary data suggest that RBM3 mRNA levels are reduced in human HD brain. In cell models, RBM3 overexpression protects against polyQ-induced cell death. This suggests that RBM3 plays a role both in HD pathogenesis and neuroprotection. In addition, RBM3 overexpression plays a neuroprotective role in murine models of other neurodegenerative diseases, including Alzheimer's disease and prion disease, supporting a broad beneficial role for RBM3. Based on this data, I hypothesize that RBM3 dysregulation plays a role in the HD pathological cascade and that RBM3 overexpression will alleviate HD pathogenesis.
My first aim i s to examine the mechanism of RBM3 dysregulation and dysfunction in the setting of the mHTT allele in vitro. I will characterize RBM3 localization, distribution and co-localization with mHTT to determine whether RBM3 is sequestered by mHTT or improperly trafficked in HD cells. Because mHTT can directly repress transcription, I will determine whether mHTT represses RBM3 expression using in vitro assays. I will also assess RBM3's function in regulating post- transcriptional gene expression. Mammalian target of rapamycin complex 1 (mTORC1) activity is reduced in the striatum of HD patient brain and in an HD murine model. Therefore, my second aim is to investigate the disease-modifying effects of RBM3 overexpression in the striatum of HD mice and whether the positive effects of RBM3 require mTORC1 activity. To elucidate the interaction between RBM3 and mTORC1, I will overexpress RBM3 in the striatum of HD mice via AAV transduction and examine the progression of mTORC1- regulated transcriptional changes and striatal atrophy. To determine if RBM3-mediated protection depends on mTORC1 activity I will also overexpress RBM3 while inhibiting mTORC1, and assess correction of neurological phenotypes. Together, these studies will provide insight into the mechanism of pathogenesis in HD, which will be crucial for the development of therapeutic targets. Furthermore, RBM3 may emerge as a therapeutic target for conditions that broadly induce cellular stress including other common neurodegenerative diseases, as well as stroke and traumatic brain injury.

Public Health Relevance

Synapse loss is an early and common feature of multiple neurodegenerative diseases. RNA binding motif protein 3 (RBM3) is a stress response protein that promotes synaptic plasticity and cell survival. RBM3 is dysregulated in Alzheimer, prion and Huntington's disease models, suggesting that RBM3 dysregulation contributes to early synapse loss in multiple neurodegenerative diseases. Elucidating RBM3's function in regulating synaptic regeneration in Huntington's disease, a model neurodegenerative disease, would provide potential therapeutic targets for preventing early neuronal synapse loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS098739-01
Application #
9192585
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Daniel L
Project Start
2016-07-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-07-01
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104