Abstract
Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.
Highlights
Sirtuins are NAD+-dependent deacylases and lifespan determinants in several model organisms
To determine the mechanism of SIRT2-mediated protection against as we showed that SIRT2 modulates α-synuclein (aSyn) toxicity and aggregation, we hypothesized that aSyn might be acetylated and that this could be a substrate for SIRT2
Endogenous aSyn was thermoenriched from the brain of wild-type (WT) mice and evaluated by enhanced GFP; GFP, green fluorescent protein; HEK, human embryonic kidney cells; ICC, immunocytochemistry; IP, immunoprecipitated; LDH, lactate dehydrogenase; microtubule-associated protein 2 (MAP2), microtubuleassociated protein 2; MS, mass spectrometry; MW, molecular weight; NMR, nuclear magnetic resonance; PD, Parkinson disease; Scr, scramble shRNA; shRNA, short hairpin RNA; SIRT, sirtuin; SN, substantia nigra; SUV, small unilamellar vesicle; TH, tyrosine hydroxylase; ThT, thioflavin T; T2.KD, SIRT2 knockdown; T2.KO, SIRT2 knockout; WT, wild type
Summary
Sirtuins are NAD+-dependent deacylases and lifespan determinants in several model organisms. Sirtuin proteins have been implicated in neurodegenerative disorders, conditions that are strongly associated with aging [1,2]. SIRT2 is the most abundant sirtuin in the brain and its levels increase with aging [3]. SIRT2 emerged as a potential culprit in Parkinson disease (PD) pathology, as we showed that SIRT2 modulates α-synuclein (aSyn) aggregation and toxicity [4]. The balance between acetylation and deacetylation is altered in both aging and neurodegeneration, and a link between acetylation of nonhistone proteins and neuroprotection has recently emerged [6]. We provide detailed insight into the mechanism through which SIRT2 modulates aSyn toxicity and demonstrate that acetylation on lysine (K) and K10 might be used as targets for therapeutic intervention in PD and in other synucleinopathies
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