Date of Award
7-13-2016
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Bioinformatics
First Advisor
Robert Shmookler Reis
Abstract
Age-dependent neurodegenerative diseases form neurotoxic protein aggregates containing both disease-specific initiator ('seed') proteins and shared components that are common to multiple neuropathies (e.g., TDP-43, α-synuclein, hyper-phosphorylated tau). To date, the protein compositions of aggregates and the functional roles of shared components, in aggregation and disease progression, have not been fully explored. This dissertation investigated common aggregation-prone proteins, identified to promote aggregation and toxicity in multiple neurodegenerative disease models. Proteomic analysis of muscle aggregates from Caenorhabditis elegans expressing unc-54p/ Q40::YFP (a model of Huntington's disease) which forms aggregates in muscle, identified proteins that co-aggregate with long polyglutamine tracts. Functional analysis uncovered a novel protein which we termed "Cytotoxicity-related aggregation mediator-1” (CRAM-1). CRAM-1 was shown to promote aggregation in multiple C. elegans models of human neurodegenerative diseases. Both computational biology and molecular biology approaches indicated CRAM-1 blocks protein degradation by interacting with poly-ubiquitin chains via its C-terminal UBA-like domain. SERF2, a human ortholog of CRAM-1, was shown to promote aggregation in a human cell-culture model of Alzheimer's disease, employing the same mechanism as CRAM-1.
Recommended Citation
Balasubramaniam, Meenakshisundaram Balasubramaniam, "Structural and Functional Roles of Proteins Modulating Aggregation in Multiple Neurodegenerative Diseases" (2016). Theses and Dissertations. 688.
https://research.ualr.edu/etd/688
