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ALS linked mutations in Matrin 3 alter protein-protein interactions and impede mRNA nuclear export

Description
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…

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.
ContributorsBoehringer, Ashley (Author) / Bowser, Robert (Thesis advisor) / Liss, Julie (Committee member) / Jensen, Kendall (Committee member) / Ladha, Shafeeq (Committee member) / Arizona State University (Publisher)
Created2018
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An Algorithm for the Automatic Detection of Vocal Flutter

Description
Detecting early signs of neurodegeneration is vital for measuring the efficacy of pharmaceuticals and planning treatments for neurological diseases. This is especially true for Amyotrophic Lateral Sclerosis (ALS) where differences in symptom onset can be indicative of the prognosis. Because it can be measured noninvasively, changes in speech production have…

Detecting early signs of neurodegeneration is vital for measuring the efficacy of pharmaceuticals and planning treatments for neurological diseases. This is especially true for Amyotrophic Lateral Sclerosis (ALS) where differences in symptom onset can be indicative of the prognosis. Because it can be measured noninvasively, changes in speech production have been proposed as a promising indicator of neurological decline. However, speech changes are typically measured subjectively by a clinician. These perceptual ratings can vary widely between clinicians and within the same clinician on different patient visits, making clinical ratings less sensitive to subtle early indicators. In this paper, we propose an algorithm for the objective measurement of flutter, a quasi-sinusoidal modulation of fundamental frequency that manifests in the speech of some ALS patients. The algorithm detailed in this paper employs long-term average spectral analysis on the residual F0 track of a sustained phonation to detect the presence of flutter and is robust to longitudinal drifts in F0. The algorithm is evaluated on a longitudinal speech dataset of ALS patients at varying stages in their prognosis. Benchmarking with two stages of perceptual ratings provided by an expert speech pathologist indicate that the algorithm follows perceptual ratings with moderate accuracy and can objectively detect flutter in instances where the variability of the perceptual rating causes uncertainty.
ContributorsPeplinski, Jacob Scott (Author) / Berisha, Visar (Thesis director) / Liss, Julie (Committee member) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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Vowel Normalization in Dysarthria

Description
In this study, the Bark transform and Lobanov method were used to normalize vowel formants in speech produced by persons with dysarthria. The computer classification accuracy of these normalized data were then compared to the results of human perceptual classification accuracy of the actual vowels. These results were then analyzed…

In this study, the Bark transform and Lobanov method were used to normalize vowel formants in speech produced by persons with dysarthria. The computer classification accuracy of these normalized data were then compared to the results of human perceptual classification accuracy of the actual vowels. These results were then analyzed to determine if these techniques correlated with the human data.
ContributorsJones, Hanna Vanessa (Author) / Liss, Julie (Thesis director) / Dorman, Michael (Committee member) / Borrie, Stephanie (Committee member) / Barrett, The Honors College (Contributor) / Department of Speech and Hearing Science (Contributor) / Department of English (Contributor) / Speech and Hearing Science (Contributor)
Created2013-05