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To examine the role of a nuclear import protein karyopherin-β2 in FUS-mediated amyotrophic lateral sclerosis pathogenesis

Zammerilla, Christopher Patrick (2023) To examine the role of a nuclear import protein karyopherin-β2 in FUS-mediated amyotrophic lateral sclerosis pathogenesis. Master's Thesis, University of Pittsburgh. (Unpublished)

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by muscle weakness and atrophy. The gene Fused in Sarcoma (FUS) has been previously reported to be a causal agent of ALS when mutated. FUS encodes for a protein that binds to RNA that is involved in RNA processing/trafficking, alternative splicing, and DNA damage repair. When mutated FUS causes early onset and aggressive form of ALS as it mislocalizes to the cytoplasm in toxic protein aggregates.
Previous studies have shown that nucleocytoplasmic transport defects are a common pathway in FUS-mediated ALS as well as other forms of ALS. The goal of this experiment is to test Karyopherin beta 2 (KAPβ2) effect on FUS-mediated ALS. KAPβ2 is a transport protein that previous studies in vitro have shown is able to positively modify FUS-mediated ALS by decreasing FUS toxicity. Drosophila melanogaster has been used extensively as a model for ALS as it can mimic the symptoms and pathology of ALS. Multiple fly lines engineered with KAPβ2 overexpression that were modified to target the PY-NLS of FUS P525L. These lines were crossed with strains of FUS mutant flies that our lab had previously created. We found that when overexpressed with KAPβ2 flies show rescues motor function, lifespan, eye degradation. KAPβ2 expressing flies also had reduced FUS cytoplasmic localization.
Altogether, our data suggests that KAPβ2 is a modifier of FUS-induced ALS in Drosophila neurons. As KAPβ2 is a modifier of FUS-mediated ALS KAPβ2 could be used as a possible therapeutic for ALS. The public health relevance of this work is that if KAPβ2 could be used as a therapeutic for the treatment of ALS, a disease with little treatments available and no cures. This is especially relevant as the growing elderly population in many developed countries will cause more cases of ALS to arise. By having a possible therapeutic this will alleviate the stress on patients their families, healthcare workers, and healthcare systems across the world.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zammerilla, Christopher Patrickcpz7@pitt.educpz7
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPandey, Udaiudai@pitt.eduudai
Committee MemberDemirci, F Yesimfyd1@pitt.edufyd1
Committee MemberPadiath, Quasar Saleemqpadiath@pitt.eduqpadiath
Date: 24 August 2023
Date Type: Publication
Defense Date: 26 July 2023
Approval Date: 24 August 2023
Submission Date: 9 August 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 44
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: ALS, KAPB2, FUS, Nucleocytoplasmic transport
Date Deposited: 24 Aug 2023 17:02
Last Modified: 24 Aug 2023 17:02


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