Sirtuins as Modifiers of Huntington's Disease (HD) Pathology

Neo, Sin Hui; Tang, Bor Luen

doi:10.1016/bs.pmbts.2017.11.013

Cited by 20 publications

(13 citation statements)

References 322 publications

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“…phosphorylation (GSK-3β, MAPK1, CDK5/PP2B) ↑ mitochondrial fragmentation [30][31][32] S-nitrosylation ↑ mitochondrial fragmentation [33,34] Manganese superoxide dismutase (MnSOD) acetylation ↓ mitochondrial biogenesis [35,36] Lon protease acetylation ↓ degradation of aconitase [37] β-catenin phosphorylation (GSK-3, CK1) ↓ less efficient energy production [38]…”

Section: Dynamin-related Protein (Drp1)mentioning

confidence: 99%

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay

Kiss

Virág

et al. 2020

IJMS

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.

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Section: Dynamin-related Protein (Drp1)mentioning

confidence: 99%

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay

Kiss

Virág

et al. 2020

IJMS

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“…Sirtuins are surely involved in the neurodegenerative process in HD, however, there are controversial results regarding their role [36,38,45,61]. Further studies are needed to clarify these controversies and to better explore the role of different Sirtuin subtypes and isoforms obtained by alternative splicing [2,22,24,27,36,56].…”

Section: Discussionmentioning

confidence: 99%

“…Sirtuins are class III NAD + -dependent deacetylases [38]. Currently there are seven identified mammalian Sirtuin subtypes (SIRT1-7), which are localized in different cellular compartments (nuclear: SIRT1 (the mammalian orthologue of the yeast Silent information regulator 2 protein (Sir2)), -6, -7; mitochondrial: SIRT3, -4, -5; cytoplasmatic: SIRT2) [36].…”

Section: Introductionmentioning

confidence: 99%

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Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington’s Disease

et al. 2020

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The potential role of Sirt1 and Sirt2 subtypes of Sirtuins (class III NAD +-dependent deacetylases) in the pathogenesis of Huntington's disease (HD) has been extensively studied yielding some controversial results. However, data regarding the involvement of Sirt3 and their variants in HD are considerably limited. The aim of this study was to assess the expression pattern of Sirt1 and three Sirt3 mRNA isoforms (Sirt3-M1/2/3) in the striatum, cortex and cerebellum in respect of the effect of gender, age and the presence of the transgene using the N171-82Q transgenic mouse model of HD. Striatal, cortical and cerebellar Sirt1-Fl and Sirt3-M1/2/3 mRNA levels were measured in 8, 12 and 16 weeks old N171-82Q transgenic mice and in their wild-type littermates. Regarding the striatum and cortex, the presence of the transgene resulted in a significant increase in Sirt3-M3 and Sirt1 mRNA levels, respectively, whereas in case of the cerebellum the transgene resulted in increased expression of all the assessed subtypes and isoforms. Aging exerted minor influence on Sirt mRNA expression levels, both in transgene carriers and in their wild-type littermates, and there was no interaction between the presence of the transgene and aging. Furthermore, there was no difference between genders. The unequivocal cerebellar Sirtuin activation with presumed compensatory role suggests that the cerebellum might be another key player in HD in addition to the most severely affected striatum. The mitochondrially acting Sirt3 may serve as an interesting novel therapeutic target in this deleterious condition.

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“…Importantly, SIRT1 has been shown to regulate metabolism and longevity through hypothalamic circuitries and also regulates the maturation of hypothalamic peptide hormones controlling energy balance and their processing enzymes . SIRTs, in particular SIRT1, SIRT2 and SIRT3, have been suggested to play a role in HD but the published results are conflicting and the effects on expression levels in HD patients are not well known . Interestingly, it has been shown that treatment with SIRT1 inhibitors is neuroprotective in Drosophila, mammalian cells and mouse models of HD .…”

Section: Introductionmentioning

confidence: 99%

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

Baldo

Gabery

Soylu-Kucharz

et al. 2018

Neuropathology Appl Neurobio

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Sirtuins as Modifiers of Huntington's Disease (HD) Pathology

Cited by 20 publications

References 322 publications

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington’s Disease

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

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