Author : Joseph Ochaba
Publisher :
ISBN 13 : 9781369174205
Total Pages : 254 pages
Book Rating : 4.1/5 (742 download)
Book Synopsis Finding Balance in Huntington's Disease by : Joseph Ochaba
Download or read book Finding Balance in Huntington's Disease written by Joseph Ochaba and published by . This book was released on 2016 with total page 254 pages. Available in PDF, EPUB and Kindle. Book excerpt: The disruption of protein quality control networks that ensure proper folding and degradation of cellular proteins is likely central to pathology in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other "protein misfolding" diseases (La Spada and Taylor, 2010; Wilkinson et al., 2010). A detailed understanding of the proteostasis network components and their contributions to pathology are therefore crucial to developing improved therapeutic interventions. HD is caused by the abnormal expansion of a CAG repeat within the HD gene resulting in an expanded stretch of polyglutamines in the Huntingtin (HTT) protein (Group, 1993a). A key pathological feature is the accumulation of mutant HTT protein (mHTT) (Cisbani and Cicchetti, 2012; Zhao et al., 2016). Post-translational modifications of HTT, including SUMOylation and phosphorylation (Ehrnhoefer et al., 2011; Pennuto et al., 2009), appear to contribute to mechanisms underlying mHTT function, clearance, and accumulation (O'Rourke et al., 2013; Ochaba et al., 2016; Zhao et al., 2016).The work presented here represents an innovative conceptual shift to address questions fundamental to HD and other diseases where protein homeostasis is affected. This approach may therefore provide insight into a broad spectrum of protein misfolding disorders. My dissertation utilized gain-of and loss-of-function approaches to query the importance of HTT function, modulation of PIAS1-regulatory networks, and SUMO-interaction motifs in the context of cell culture and in vivo mouse model systems to assess the impact on critical disease regulatory networks and HD pathogenesis. The precise mechanisms involved in the aforementioned have not yet been elucidated, nor has the PIAS and SUMO pathways been tested in vivo for its relevance to the following: the accumulation of neurodegenerative disease-causing proteins, neuroinflammation, protein clearance networks, or overall impact on disease phenotypes. My dissertation suggests that PIAS1 may link protein homeostasis and neuroinflammation in HD through a combination of modulating accumulation of toxic HMW species of HTT and compensating for dysfunctional inflammatory signaling cascades between neurons and microglia, potentially allowing improved flux through protein clearance pathways, of which HTT itself is likely involved in regulating.
