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The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

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 ?-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that ?-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 ?-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate ?-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies ?-synuclein acetylation as a key regulatory mechanism governing ?-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.

SUBMITTER: de Oliveira RM

PROVIDER: S-EPMC5336201 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

de Oliveira Rita Machado RM Vicente Miranda Hugo H Francelle Laetitia L Pinho Raquel R Szegö Éva M ÉM Martinho Renato R Munari Francesca F Lázaro Diana F DF Moniot Sébastien S Guerreiro Patrícia P Fonseca-Ornelas Luis L Marijanovic Zrinka Z Antas Pedro P Gerhardt Ellen E Enguita Francisco Javier FJ Fauvet Bruno B Penque Deborah D Pais Teresa Faria TF Tong Qiang Q Becker Stefan S Kügler Sebastian S Lashuel Hilal Ahmed HA Steegborn Clemens C Zweckstetter Markus M Outeiro Tiago Fleming TF

PLoS biology 20170303 3

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 synuc ...[more]

PMID: 28257421

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Project description:BACKGROUND:Misfolding and aggregation of the presynaptic protein alpha-synuclein (?syn) is a hallmark of Parkinson's disease (PD) and related synucleinopathies. Although predominantly localized in the cytosol, a body of evidence has shown that ?syn localizes to mitochondria and contributes to the disruption of key mitochondrial processes. Mitochondrial dysfunction is central to the progression of PD and mutations in mitochondrial-associated proteins are found in familial cases of PD. The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that play a broad role in cellular metabolism and aging. Interestingly, mitochondrial sirtuin 3 (SIRT3) plays a major role in maintaining mitochondrial function and preventing oxidative stress, and is downregulated in aging and age-associated diseases such as neurodegenerative disorders. Herein, we hypothesize that ?syn is associated with decreased SIRT3 levels contributing to impaired mitochondrial dynamics and biogenesis in PD. METHODS:The level of mitochondrial SIRT3 was assessed in cells expressing oligomeric ?syn within the cytosolic and mitochondrial-enriched fractions. Mitochondrial integrity, respiration, and health were examined using several markers of mitochondrial dynamics and stress response and by measuring the rate of oxygen consumption (OCR). Our findings were validated in a rodent model of PD as well as in human post-mortem Lewy body disease (LBD) brain tissue. RESULTS:Here, we demonstrate that ?syn associates with mitochondria and induces a decrease in mitochondrial SIRT3 levels and mitochondrial biogenesis. We show that SIRT3 downregulation is accompanied by decreased phosphorylation of AMPK and cAMP-response element binding protein (CREB), as well as increased phosphorylation of dynamin-related protein 1 (DRP1), indicative of impaired mitochondrial dynamics. OCR was significantly decreased suggesting a mitochondria respiratory deficit. Interestingly treatment with AMPK agonist 5-aminoimidazole-4-carboxamide-1-?-d-ribofuranoside (AICAR) restores SIRT3 expression, improves mitochondrial function, and decreases ?syn oligomer formation in a SIRT3-dependent manner. CONCLUSIONS:Together, our findings suggest that pharmacologically increasing SIRT3 levels can counteract ?syn-induced mitochondrial dysfunction by reducing ?syn oligomers and normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in PD-associated pathways and contribute significant mechanistic insight into the interplay of SIRT3 and ?syn.

Dataset Information

The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

Publications

The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

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