Despite uncertainty surrounding the exact molecular cause of neurodegeneration, a common feature is the accumulation and aggregation of neuronal protein fragments resulting from an increase in their production, or a decrease in their removal. The overall goal of this research is to understand the effects of aggregation-prone protein fragments on normal cell function and to identify cellular pathways involved in the removal of toxic protein species. Previously we found that the N-end rule pathway of the ubiquitin-proteasome system is able to degrade specific protein fragments associated Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and frontotemporal lobar degeneration. This exciting discovery suggests that defects in the N-end rule pathway may contribute to neurodegeneration. To test this, we will investigate the transgenic expression of a specific disease-associated fragment of the human TDP43 protein in a number of settings including mice, yeast, and in cell culture. These studies will determine if protein fragments of TDP43 play a causative role in disease, and if the loss of their removal by the N-end rule pathway leads to neurodegeneration, in vivo. In addition, these studies generate a number of genetic tools, including a novel mouse model, that will be a valuable resource for the neurodegeneration field, and may ultimately help lead to therapies aimed at preventing neurodegeneration in humans.
Despite uncertainty surrounding the exact molecular cause of neurodegeneration, a common feature is the accumulation and aggregation of neuronal protein fragments. This research will investigate the mechanism by which protein fragments may cause disease, and the cellular pathways that exist to remove toxic protein fragments. This research may ultimately contribute to the development of therapies aimed at preventing or reversing neurodegenerative disease in humans.
| Kasu, Yasar Arfat T; Alemu, Samrawit; Lamari, Angela et al. (2018) The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology. Mol Cell Biol 38: |
