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Project
Role of ubiquitination in phase transitions in Amyotrophic Lateral Sclerosis (ALS) (FWOTM959)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by the appearance of ubiquitinated protein inclusions in affected motor neurons. The main protein component of these inclusions is an RNA-binding protein called Transactivation response [Tar]-DNA-binding protein, 43 kDa (TDP-43). The consensus is that protein ubiquitination in ALS inclusions is a sign of a failed attempt by the cell to degrade misfolded/aggregated proteins via the ubiquitin-proteasome system (UPS) or autophagy. However, we hypothesize that protein components of ALS-associated inclusions may carry ubiquitin-binding motifs/domains that could promiscuously interact with ubiquitin
chains placed on inclusion body proteins to tilt the balance in favor of protein aggregation. To test this hypothesis, we collected data on all known ALS-inclusion proteins and screened for previously reported ubiquitin-binding proteins or proteins that harbor ubiquitin-binding domains. From these screens, eleven ubiquitin-binding proteins and seven proteins with known ubiquitin-binding domains were identified. The next steps will involve screening of the strongest ubiquitin binders, whose interaction with TDP-43 will later be assessed in the presence and absence of ubiquitination. Finally, we would like to understand how ubiquitination influences the formation of active biomolecular condensates under physiological conditions that later mediate protein aggregation during disease progression.
chains placed on inclusion body proteins to tilt the balance in favor of protein aggregation. To test this hypothesis, we collected data on all known ALS-inclusion proteins and screened for previously reported ubiquitin-binding proteins or proteins that harbor ubiquitin-binding domains. From these screens, eleven ubiquitin-binding proteins and seven proteins with known ubiquitin-binding domains were identified. The next steps will involve screening of the strongest ubiquitin binders, whose interaction with TDP-43 will later be assessed in the presence and absence of ubiquitination. Finally, we would like to understand how ubiquitination influences the formation of active biomolecular condensates under physiological conditions that later mediate protein aggregation during disease progression.
Date:1 Nov 2019 → 31 Jan 2024
Keywords:Amiotrophic lateral sclerosis, ALS
Disciplines:Molecular and cell biology not elsewhere classified, Posttranslational modifications, Other biotechnology, bio-engineering and biosystem engineering not elsewhere classified