Investigating the dysregulation and therapeutic potential of neuroprotective stress response proteins in Huntington's disease / Julianne Margaret Rieders.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Rieders, Julianne Margaret, author.

Contributor:

Davidson, Beverly L., degree supervisor.

Arruda, Valder R., degree committee member.

Bennett, Jean, degree committee member.

Bonini, Nancy, degree committee member.

Brown, Eric J., degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

ix, 115 leaves : color illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2019.

Summary:

Huntington's disease (HD) is a fatal, genetic neurodegenerative disease that shares many features with other common neurological disorders, including early synapse loss. In both human HD brain and murine models, apoptotic pathways are dysregulated and mammalian target of rapamycin complex 1 (mTORC1) activity is reduced. These pathways are of particular interest because they regulate cell survival and metabolism, and enhancing mTORC1 is protective in HD models. RNA binding motif protein 3 (RBM3) is a stress response protein that promotes synaptic plasticity and cell survival, and is dysregulated in Alzheimer, prion and HD models. Hippocampal overexpression of RBM3 in Alzheimer and prion murine models is neuroprotective and in the setting of prion disease is mediated by reticulon 3 (RTN3), a downstream target of RBM3. Here, I show that RBM3 and RTN3 are dysregulated in in vitro and in vivo models of HD. I find that overexpressing RBM3 isoform 1 or RTN3 in the striatum of HD mice does not rescue disease phenotypes. I also find that overexpressing RBM3 isoform 1 or 2 in the striatum does not increase RTN3 levels as expected. Further, I provide evidence that cold stress and RBM3 overexpression enhances components of the mTORC1 pathway in vitro and in vivo. My combined work indicates that the RBM3-RTN3 axis may function differently in the striatum, possibly contributing to striatal vulnerability in HD, and that while RBM3 enhances components of the mTORC1 pathway, it is insufficient to rescue HD phenotypes.

Notes:

Ph. D. University of Pennsylvania 2019.

Department: Cell and Molecular Biology.

Supervisor: Beverly L. Davidson.

Includes bibliographical references.

Other Format:

Online version: Rieders, Julianne Margaret. Investigating the dysregulation and therapeutic potential of neuroprotective stress response proteins in Huntington's disease.

OCLC:

1125984230