| Description |
The unstable expansion of the polyglutamine (polyQ) tract is a critical factor in the pathogenic pathway of at least ten neurodegenerative diseases, including Huntington's disease, spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and seven spinocerebellar ataxias, all of which are termed as polyglutamine diseases. One less understood but common feature of polyQ diseases is polyQ protein aggregation. This dissertation explores the protein folding, hydrogen bonding, and water accessibility changes which are induced by the enlargement of the polyQ tract using advanced informatics and computational methods, including protein 3D structure modeling and molecular dynamics simulations. This dissertation also demonstrates that these state-of-the-art computational and informatics methods are powerful tools to provide useful insights into protein aggregation in polyQ diseases. The enlargement of polyQ segments affects both local and global structures of polyQ proteins as well as their water-accessibility, hydrogen bond patterns, and other structural characteristics. Results from both isolated polyQ and polyQ segments in the context of ataxin-2 and ataxin-3 show that the polyQ tracts increasingly prefer self-interaction as the lengths of the tracts increase, indicating an increased tendency toward aggregation among larger polyQ tracts. These results provide new insights into possible pathogenic mechanisms of polyQ diseases based solely on the increased propensity toward polyQ aggregation and suggest that the modulation of solvent-polyQ interaction may be a possible therapeutic strategy for treating polyQ diseases. The analysis pipeline designed and used in this study is an effective way to study the molecular mechanism of polyQ diseases, and can be generalized to study other diseases associated with the protein conformation changes, such as Parkinson's disease, Alzheimer's disease, and cancer. |
