Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS‐linked mutant SOD1

Harlan, Benjamin A.; Pehar, Mariana; Killoy, Kelby M.; Vargas, Marcelo R.

doi:10.1096/fj.201802752r

Cited by 43 publications

(30 citation statements)

References 54 publications

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“…The overexpression of NAD + dependent deacetylase SIRT6 and SIRT3 can eliminate the neurotoxicity in the astrocyte cultured in vitro by activating the Nrf2-mediated antioxidant defenses. 556 Interestingly, the expression of SIRT1 in the spinal cord of WT mouse is reduced during normal aging, while the expression of SIRT1 in different regions of the brain (including the spinal cord, hippocampus, thalamus and cerebral cortex) in SOD1G93A mouse is increased. 557 Besides, overexpression of SIRT1 in motor neurons slows down the progression of ALS in severely phenotypic SOD1G93A (with high copy numbers) mice, partly by activating the HSF1/HSP70i molecular chaperone system.…”

Section: Abnormal Nad + Metabolism In the Pathophymentioning

confidence: 97%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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Section: Abnormal Nad + Metabolism In the Pathophymentioning

confidence: 97%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

551

383

View full text Add to dashboard Cite

show abstract

“…The animals also exhibited other complications such as curved spines, decreased subcutaneous fat, hypoglycemia, and lowered levels of IGF-1 ( Peshti et al, 2017 ; Khan R. I. et al, 2018 ; Ghosh et al, 2018 ; Simon et al, 2019 ). This suggests that Sirt6 is a therapeutic target in aging, cardiac disorders, neurodegenerative disorders, and metabolic disorders ( Rodgers and Puigserver, 2006 ; Serravallo et al, 2013 ; Demir et al, 2017 ; Harlan et al, 2019 ). Table 1 .…”

Section: Sirt6 and Diseasesmentioning

confidence: 99%

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

et al. 2020

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Sirtuins, NAD + dependent proteins belonging to class III histone deacetylases, are involved in regulating numerous cellular processes including cellular stress, insulin resistance, inflammation, mitochondrial biogenesis, chromatin silencing, cell cycle regulation, transcription, and apoptosis. Of the seven mammalian sirtuins present in humans, Sirt6 is an essential nuclear sirtuin. Until recently, Sirt6 was thought to regulate chromatin silencing, but new research indicates its role in aging, diabetes, cardiovascular disease, lipid metabolism, neurodegenerative diseases, and cancer. Various murine models demonstrate that Sirt6 activation is beneficial in alleviating many disease conditions and increasing lifespan, showing that Sirt6 is a critical therapeutic target in the treatment of various disease conditions in humans. Sirt6 also regulates the pathogenesis of multiple diseases by acting on histone proteins and non-histone proteins. Endogenous and non-endogenous modulators regulate both activation and inhibition of Sirt6. Few Sirt6 specific non-endogenous modulators have been identified. Hence the identification of Sirt6 specific modulators may have potential therapeutic roles in the diseases described above. In this review, we describe the development of Sirt6, the role it plays in the human condition, the functional role and therapeutic importance in disease processes, and specific modulators and molecular mechanism of Sirt6 in the regulation of metabolic homeostasis, cardiovascular disease, aging, and neurodegenerative disease.

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“…RNA extraction, RNA retrotranscription, real‐time PCR, and western blot analysis were performed as previously described (Harlan, Pehar, Killoy, & Vargas, 2019). Membranes were incubated overnight with one of the following antibodies: FABP7 (Thermo Fisher, Cat#: PA5‐24949, TL2690549A), actin (Sigma, A5441, lot: 061M4808), or GADPH (Sigma, SAB2100894, lot: QC9353).…”

Section: Methodsmentioning

confidence: 99%

FABP7 upregulation induces a neurotoxic phenotype in astrocytes

Killoy

Harlan

Pehar

et al. 2020

Glia

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Fatty acid binding proteins (FABPs) are key regulators of lipid metabolism, energy homeostasis, and inflammation. They participate in fatty acid metabolism by regulating their uptake, transport, and availability of ligands to nuclear receptors. In the adult brain, FABP7 is especially abundant in astrocytes that are rich in cytoplasmic granules originated from damaged mitochondria. Mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process observed in amyotrophic lateral sclerosis (ALS), either as a primary cause or as a secondary component of the pathogenic process. Here we investigated the expression of FABP7 in animal models of human superoxide dismutase 1 (hSOD1)-linked ALS. In the spinal cord of symptomatic mutant hSOD1-expressing mice, FABP7 is upregulated in gray matter astrocytes. Using a coculture model, we examined the effect of increased FABP7 expression in astrocyte-motor neuron interaction. Our data show that FABP7 overexpression directly promotes an NF-κB-driven pro-inflammatory response in nontransgenic astrocytes that ultimately is detrimental for motor neuron survival. Addition of trophic factors, capable of supporting motor neuron survival in pure cultures, did not prevent motor neuron loss in cocultures with FABP7 overexpressing astrocytes. In addition, astrocyte cultures obtained from symptomatic hSOD1-expressing mice display upregulated FABP7 expression. Silencing endogenous FABP7 in these cultures decreases the expression of inflammatory markers and their toxicity toward cocultured motor neurons. Our results identify a key role of FABP7 in the regulation of the inflammatory response in astrocytes and identify FABP7 as a potential therapeutic target to prevent astrocyte-mediated motor neuron toxicity in ALS.

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Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS‐linked mutant SOD1

Cited by 43 publications

References 54 publications

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

FABP7 upregulation induces a neurotoxic phenotype in astrocytes

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