Altered SIRT4 Expression Is Associated with Lewy Body Pathology (P01.209)

Objective: We conducted a gene expression study to survey members of the sirtuin family in postmortem brains that met neuropathologic criteria for the diagnosis of Parkinson9s disease (PD) and diffuse Lewy body dementia (DLB). Background Sirtuins have emerged as therapeutic targets to treat age-related diseases. The expression profile of sirtuins has only recently been examined postmortem in neurodegenerative disorders. Recent discoveries of small-molecule and protein modulators of sirtuin deacetylation activity have validated their potential as therapeutics to alter disease progression. Design/Methods: Sirtuin expression analysis was examined by quantitative real-time polymerase chain reaction in postmortem brain. We surveyed seven sirtuin (SIRT1-7) gene products in the caudate and insular cortex sampled from age-matched non-neurologic control subjects (N = 10), PD (N = 9) and DLB subjects (N = 9). Results: In PD, only SIRT4 expression was significantly changed in the caudate (fold change (FC) = 2.1, p=0.01) when compared with controls, but not in the insular cortex. In DLB cases, a synucleinopathy with more widespread cortical involvement, SIRT4 upregulation was robust in both the caudate and insula (FC = 2.4, p=0.003). We confirmed that SIRT4 was elevated in a second independent cohort of PD and control subjects (n = 17; FC = 2.0, p=0.0006). Taken together, the results demonstrate that SIRT4 dysregulation maybe a marker of Lewy body disease, since there was no trend observed for the other members of the sirtuin family. Conclusions: SIRT4 is a mitochondrial sirtuin involved in regulating OXPHOS capacity in response to caloric restriction. Although inhibition of SIRT2 has been shown to modify inclusion morphology in a cellular model of Parkinson9s disease, this member of the sirtuin family is unaffected in human brain. SIRT4 downregulation has been associated with increased mitochondrial oxidative phosphorylation capacity, suggesting a role for this member of the sirtiun family in synucleinopathies. Supported by: Funded by the Francis and Morris McGowan Trust (DCM). Disclosure: Dr. Luca has nothing to disclose. Dr. Garamszegi has nothing to disclose. Dr. Eldick has nothing to disclose. Dr. Singer has received personal compensation for activities with Ipsen, Allergan, Merz, and Lundbeck. Dr. Singer has received research support from Schwarz Pharma, Synosia, Allergan, Astellas, and Boehringer Ingelheim. Dr. Mash has nothing to disclose.