SIRT2: in the crossroad of aging, neurodegeneration and autophagy
Year: 2013
Type: dissertation
Abstract: Sirtuin 2 (SIRT2) is the most abundant sirtuin in the brain and its relation with neurodegenerative diseases is now being intensively investigated (Maxwell et al., 2011). In particular, pharmacological inhibition of SIRT2 was shown to negatively modulate α-synuclein (aSyn) mediated toxicity (Outeiro et al., 2007). However, it is not clear how this is achieved. One possibility is that the presence of SIRT2 may be a limiting factor for aSyn aggregate clearance. Macroautophagy is involved in the clearance of aggregates such as those found in Parkinson’s Disease, that cannot be processed by the proteasome (Lynch-Day et al., 2012; Snyder et al., 2003). Furthermore, SIRT1 positively regulates autophagy and, in the context of cancer, SIRT2 was shown to negatively modulate autophagy in a FOXO1 dependent manner (Lee et al., 2008; Zhao et al., 2010a, 2010b). Thus, we proposed to study the effect of SIRT2 on the modulation of autophagy in the presence of aSyn inclusions. For this study we used the H4 (neuroglioma) cell line co-expressing a C-terminally-modified version of aSyn (SynT) and synphilin-1 to study the effect of SIRT2 on aSyn inclusion formation. Also, we established a model for the study of autophagy in H4 cells that we used to determine the effects of SIRT2 knock-down (T2KD) on autophagy. Finally, we studied the effects of SIRT2 on autophagy in the presence of aSyn inclusions. We showed that there are less T2KD cells with inclusions, when compared with control (Ctrl) cells. We also showed that in the absence of aggregates T2KD cells have a more efficient drug-dependent induction of autophagy and basal autophagy is not affected. Finally, we prove that aSyn inclusion-dependent induction of autophagy is more effective in T2KD cells. Our findings suggest that SIRT2 may limit autophagy induction, supporting a beneficial role for SIRT2 inhibition in models of Parkinson Disease.
Author: Renato Martinho
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2237886719