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Sirtuin deacetylases in neurodegenerative diseases of aging.

Herskovits AZ, Guarente L - Cell Res. (2013)

Bottom Line: Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity.Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy.Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA.

ABSTRACT
Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.

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Related in: MedlinePlus

Sirtuin targets in motor neuron diseases. (A) In the SOD1 G93A mouse model of amyotrophic lateral sclerosis, intraperitoneal injection of resveratrol is protective. The proposed mechanism is that SIRT1 can deacetylate HSF1, inducing transcription of hsp70 and hsp25. Induction of these heat shock proteins decrease proteotoxic stress from misfolded protein aggregates11,70,75,111. SIRT3 and PGC-1α were also shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression in cell culture115. (B) In spinal and bulbar muscular atrophy (SBMA), the polyglutamine-expanded androgen receptor can be directly deacetylated by SIRT1 at lysines 630, 632, and 633. It has been shown that deacetylation of the androgen receptor at these residues can decrease aggregation and toxicity in cellular models of SBMA124.
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fig5: Sirtuin targets in motor neuron diseases. (A) In the SOD1 G93A mouse model of amyotrophic lateral sclerosis, intraperitoneal injection of resveratrol is protective. The proposed mechanism is that SIRT1 can deacetylate HSF1, inducing transcription of hsp70 and hsp25. Induction of these heat shock proteins decrease proteotoxic stress from misfolded protein aggregates11,70,75,111. SIRT3 and PGC-1α were also shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression in cell culture115. (B) In spinal and bulbar muscular atrophy (SBMA), the polyglutamine-expanded androgen receptor can be directly deacetylated by SIRT1 at lysines 630, 632, and 633. It has been shown that deacetylation of the androgen receptor at these residues can decrease aggregation and toxicity in cellular models of SBMA124.

Mentions: A recent paper identified SIRT3 as a relevant player in ALS pathogenesis using a cell-based model. SIRT3 was shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression115. The major mechanisms that have been proposed for sirtuins in ALS pathogenesis are diagrammed in Figure 5A. Additional research confirming the effect of pharmacologic intervention in animal models of ALS will be important in evaluating whether sirtuin modulatory compounds should enter the human clinical trial pipeline.


Sirtuin deacetylases in neurodegenerative diseases of aging.

Herskovits AZ, Guarente L - Cell Res. (2013)

Sirtuin targets in motor neuron diseases. (A) In the SOD1 G93A mouse model of amyotrophic lateral sclerosis, intraperitoneal injection of resveratrol is protective. The proposed mechanism is that SIRT1 can deacetylate HSF1, inducing transcription of hsp70 and hsp25. Induction of these heat shock proteins decrease proteotoxic stress from misfolded protein aggregates11,70,75,111. SIRT3 and PGC-1α were also shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression in cell culture115. (B) In spinal and bulbar muscular atrophy (SBMA), the polyglutamine-expanded androgen receptor can be directly deacetylated by SIRT1 at lysines 630, 632, and 633. It has been shown that deacetylation of the androgen receptor at these residues can decrease aggregation and toxicity in cellular models of SBMA124.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674397&req=5

fig5: Sirtuin targets in motor neuron diseases. (A) In the SOD1 G93A mouse model of amyotrophic lateral sclerosis, intraperitoneal injection of resveratrol is protective. The proposed mechanism is that SIRT1 can deacetylate HSF1, inducing transcription of hsp70 and hsp25. Induction of these heat shock proteins decrease proteotoxic stress from misfolded protein aggregates11,70,75,111. SIRT3 and PGC-1α were also shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression in cell culture115. (B) In spinal and bulbar muscular atrophy (SBMA), the polyglutamine-expanded androgen receptor can be directly deacetylated by SIRT1 at lysines 630, 632, and 633. It has been shown that deacetylation of the androgen receptor at these residues can decrease aggregation and toxicity in cellular models of SBMA124.
Mentions: A recent paper identified SIRT3 as a relevant player in ALS pathogenesis using a cell-based model. SIRT3 was shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1 G93A overexpression115. The major mechanisms that have been proposed for sirtuins in ALS pathogenesis are diagrammed in Figure 5A. Additional research confirming the effect of pharmacologic intervention in animal models of ALS will be important in evaluating whether sirtuin modulatory compounds should enter the human clinical trial pipeline.

Bottom Line: Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity.Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy.Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA.

ABSTRACT
Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders.

Show MeSH
Related in: MedlinePlus