Protein aggregation and inclusion body formation are hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS). These neurodegenerative diseases share a common pathology in that all include accumulation of insoluble protein aggregates in the brain. TAR-DNA-binding protein (TDP-43) is the major component found in the pathological inclusions of two of these diseases, ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). This thesis focuses upon the biophysical basis for TDP-43 aggregation in S. cerevisiae. Current in vitro evidence indicates that TDP-43 is a natively dimeric protein and that binding to RNA inhibits aggregation. Corresponding genetic results in yeast in which specific components of the RNA-decay machinery have been knocked-out, indicate that the buildup of specific cellular RNAs is capable of counteracting TDP-43 aggregation and toxicity in vivo. This thesis provides evidence of separate pathologies of TDP-43 and TDP-43 mutants in S. Cerevisiae. This thesis also introduces preliminary data of the effect of in vitro synthesized RNA on TDP-43 toxicity.
","abstract_html":"<p>Protein aggregation and inclusion body formation are hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS). These neurodegenerative diseases share a common pathology in that all include accumulation of insoluble protein aggregates in the brain. TAR-DNA-binding protein (TDP-43) is the major component found in the pathological inclusions of two of these diseases, ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). This thesis focuses upon the biophysical basis for TDP-43 aggregation in <em>S. cerevisiae</em>. Current <em>in vitro</em> evidence indicates that TDP-43 is a natively dimeric protein and that binding to RNA inhibits aggregation. Corresponding genetic results in yeast in which specific components of the RNA-decay machinery have been knocked-out, indicate that the buildup of specific cellular RNAs is capable of counteracting TDP-43 aggregation and toxicity <em>in vivo</em>. This thesis provides evidence of separate pathologies of TDP-43 and TDP-43 mutants in <em>S. Cerevisiae</em>. This thesis also introduces preliminary data of the effect of <em>in vitro</em> synthesized RNA on TDP-43 toxicity.</p>","abstract_has_math":false,"creators":["Aguilar, Martin Anthony"],"institution":null,"degree_name":"M.S.","degree_level":"Masters Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Erich G. Chapman, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-01-01T08:00:00Z","date_published":"2018-01-01T08:00:00Z","updated_at":"2026-07-24T02:03:35Z","subjects":["Amyotrophic lateral sclerosis","Protein aggregation","TDP-43","TAR-DNA-binding protein","Biochemistry, Biophysics, and Structural Biology","Neuroscience and Neurobiology"],"languages":["en"],"rights":["Copyright is held by the author. User is responsible for all copyright compliance.
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"],"dc:subject":["Amyotrophic lateral sclerosis","Protein aggregation","TDP-43","TAR-DNA-binding protein","Biochemistry, Biophysics, and Structural Biology","Neuroscience and Neurobiology"],"dc:title":["Relationship Between TDP-43 Toxicity and Aggregation in Saccharomyces Cerevisiae"],"thesis:degree_level":["Masters Thesis"],"thesis:degree_name":["M.S."]},"updated_at":"2026-07-24T02:03:35Z"}