Sirtuins as Modifiers of Huntington's Disease (HD) Pathology.

Abstract

Sirtuins and their pharmacological activators/inhibitors have been associated with a range of neuroprotective effects or disease modifying influences in neurological disorders. Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disease characterized by movement disorder, psychiatric symptoms and cognitive decline. The monogenic mutation in HD encodes a variant of the protein Huntingtin (HTT). The disease is a consequence of a CAG repeat extension leading to an abnormally long polyglutamine (Q) stretch at HTT's N-terminus, which likely confers a toxic gain of function to the mutant polypeptide. HD has currently no effective disease-modifying therapy or preventive measures. In the past 2decades, a sizable body of work on Sirtuins' modification of HD pathology using HD cell and animal models has accumulated. In this chapter, evidence for Sirtuin activities as potential modifiers of HD pathology is reviewed. The conflicting findings of the impacts of mammalian Sirtuin paralogs on HD pathogenesis and disease progression are highlighted. The possible cellular and molecular mechanisms underlying Sirtuin activities in HD are discussed with reference to pathophysiological mechanisms of transcription perturbation, proteostasis, mitochondrial function, and microtubule dynamics. A brief therapeutic perspective on the use of Sirtuin activators and inhibitors is also presented.