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.