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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The role of matrin 3 in the pathogenesis of amyotrophic lateral sclerosis

Wang, Hao 08 April 2016 (has links)
The cause of amyotrophic lateral sclerosis (ALS), a cruel neurodegenerative disease, remains unclear. Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) has been suggested to have an important role in ALS pathogenesis. In this thesis, we show that a disease linked mutation in matrin 3 (MATR3), a DNA/RNA-binding protein, corresponds to an increased tendency for TDP-43 to aggregate into large and more numerous cytoplasmic inclusions that are the hallmark of ALS. Immunocytochemistry experiments show that MATR3 colocalizes with TDP-43 in vitro. These experiments also show TDP-43 is a component of both MATR3 granules and stress granules, and that MATR3 inclusions are directly adjacent to stress granules or eIF3α inclusions. We hypothesize that, while not being a part of stress granule complex, MATR3 granules are involved in RNA processing via the stress granule pathway by relaying crucial components such as TDP-43. We have also found that compound 8J is able to disaggregate and relocate TDP-43 and MATR3 positive inclusions in vitro. While the mechanism of action of compound 8J remains unclear, fluorescence activated cell sorting (FACS) experiment showed that there was a significant increase in viability in double wild type (matrin 3 and TDP-43) cells when treated with C8J (p-value <.001), which suggests that the TDP-43 and MATR3 cytoplasmic inclusions that were previously observed have a net cytotoxic effect. Together with the in vitro result on C8J, this result also suggests that C8J enhances the survivability of cells by restoring TDP-43 back to the nucleus. MATR3 biochemistry seems to connect to neurodegenerative diseases in several ways. Identifying the pathological connections between MATR3 and TDP-43 physiology will provide us with a greater understanding of ALS pathology.
2

Modeling ALS-associated Matrin-3 toxicity in yeast

El-Zein, Widad 02 August 2022 (has links)
No description available.
3

ALS Linked Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

January 2018 (has links)
abstract: Exome sequencing was used to identify novel variants linked to amyotrophic lateral sclerosis (ALS), in a family without mutations in genes previously linked to ALS. A F115C mutation in the gene MATR3 was identified, and further examination of other ALS kindreds identified an additional three mutations in MATR3; S85C, P154S and T622A. Matrin 3 is an RNA/DNA binding protein as well as part of the nuclear matrix. Matrin 3 interacts with TDP-43, a protein that is both mutated in some forms of ALS, and found in pathological inclusions in most ALS patients. Matrin 3 pathology, including mislocalization and rare cytoplasmic inclusions, was identified in spinal cord tissue from a patient carrying a mutation in Matrin 3, as well as sporadic ALS patients. In an effort to determine the mechanism of Matrin 3 linked ALS, the protein interactome of wild-type and ALS-linked MATR3 mutations was examined. Immunoprecipitation followed by mass spectrometry experiments were performed using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify ALS-causing mutations in the gene MATR3, as well as a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018

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