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dc.contributor.authorWang, Haoen_US
dc.date.accessioned2016-05-04T17:22:48Z
dc.date.available2016-05-04T17:22:48Z
dc.date.issued2015
dc.identifier.urihttps://hdl.handle.net/2144/16177
dc.description.abstractThe 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.en_US
dc.language.isoen_US
dc.subjectPharmacologyen_US
dc.subjectALSen_US
dc.subjectMATR3en_US
dc.subjectMatrin 3en_US
dc.subjectTDP43en_US
dc.subjectNeurodegenerationen_US
dc.titleThe role of matrin 3 in the pathogenesis of amyotrophic lateral sclerosisen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-04-08T20:17:04Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciences and Public Health GMSen_US
etd.degree.grantorBoston Universityen_US


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