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Full text release has been delayed at the author's request until January 20, 2025

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Dysregulation of Stress Granules in Amyotrophic Lateral Sclerosis

Dudman, Jessica
http://rave.ohiolink.edu/etdc/view?acc_num=case1673098217554181

Abstract Details

2023, Master of Sciences, Case Western Reserve University, Physiology and Biophysics.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no cure. ALS causes degeneration of both upper and lower motor neurons leading to progressive paralysis. Life expectancy after diagnosis averages 3-5 years and the current disease modifying therapies can only extend life by about 6 months (1). The exact mechanism of the pathology of ALS is unknown (2). However, the majority of cases have aggregates of TAR DNA-binding protein 43 (TDP-43), which is an RNA-binding protein (RBP), in the brain and spinal cord (3). RBPs play a special role during cellular stress by forming stress granules (SGs) through liquid-liquid phase separation. SGs are a transient, membraneless organelle that regulate RNA metabolism by separating stalled translation machinery, RNA, and RBPs from the general cytosol (4). This is a protective reaction, but in conditions of chronic stress, can become pathogenic. The TDP-43 inclusions found in patient samples co-localized with known markers of SGs, leading to the hypothesis that SGs are seeding mechanisms for protein aggregation (4). In this study, I performed qPCR analysis to determine the changes of SG-related genes in ALS patient postmortem spinal cords. I found a significant increase in DEAD-Box Helicase 3 X-Linked (DDX3X) and significant decrease in Tudor domain containing protein 3 (TDRD3) mRNA levels. Moreover, immunofluorescence staining showed that DDX3X and TDRD3 are expressed in motor neurons using Choline acetyltransferase (ChAT) as a marker for motor neurons and western blot analysis suggested that protein changes followed the mRNA changes. These findings suggest DDX3X and TDRD3 may have a role in the pathology of ALS. Thus, the overarching goal of this study is to determine the role of DDX3X and TDRD3 in ALS models, their involvement in SG mechanics, and the therapeutic viability of their manipulation. My hypothesis is that DDX3X and TDRD3 contribute to ALS pathology through their participation in pathological stress granules.
XIn Qi (Advisor)
George Dubyak (Committee Chair)
Rajesh Ramachandran (Committee Member)
Tingwei Mu (Committee Member)
Andrew Pieper (Committee Member)
38 p.
Biomedical Research
ALS; neurodegeneration; stress granules

Recommended Citations

Citations

  • Dudman, J. (2023). Dysregulation of Stress Granules in Amyotrophic Lateral Sclerosis [Master's thesis, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1673098217554181

    APA Style (7th edition)

  • Dudman, Jessica. Dysregulation of Stress Granules in Amyotrophic Lateral Sclerosis. 2023. Case Western Reserve University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1673098217554181.

    MLA Style (8th edition)

  • Dudman, Jessica. "Dysregulation of Stress Granules in Amyotrophic Lateral Sclerosis." Master's thesis, Case Western Reserve University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=case1673098217554181

    Chicago Manual of Style (17th edition)

case1673098217554181
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.