Publications by authors named "Aleksey G Kazantsev"

36 Publications

Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics.

Int J Mol Sci 2019 Mar 12;20(5). Epub 2019 Mar 12.

Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY 11794, USA.

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the genotype (rs10410544) (50.92%) and AD susceptibility in the -negative population (, 34.72%; 14.36%). The integration of and variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are (27.81%), (21.36%), (15.29%), (9.76%) and (7.18%). There is an accumulation of and carriers in > > carriers, and also of and carriers in patients who harbor the genotype. variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. carriers are the best responders, carriers show an intermediate pattern, and carriers are the worst responders to a multifactorial treatment. In bigenic clusters, carriers respond better than and carriers, whereas and carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with genophenotypes, -EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
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http://dx.doi.org/10.3390/ijms20051249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429449PMC
March 2019

The role of Nrf2 signaling in counteracting neurodegenerative diseases.

FEBS J 2018 10 29;285(19):3576-3590. Epub 2018 Jan 29.

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.
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http://dx.doi.org/10.1111/febs.14379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221096PMC
October 2018

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

Neurodegener Dis Manag 2017 04 23;7(2):97-100. Epub 2017 May 23.

Department of Neurology, Massachusetts General Hospital & Harvard Medical School; Current Effective Therapeutics, Boston, MA, USA.

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http://dx.doi.org/10.2217/nmt-2017-0011DOI Listing
April 2017

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.

Proc Natl Acad Sci U S A 2017 06 22;114(23):E4676-E4685. Epub 2017 May 22.

Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114;

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.
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http://dx.doi.org/10.1073/pnas.1614943114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468652PMC
June 2017

LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease.

J Huntingtons Dis 2016 12;5(4):347-355

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

Background: Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington's disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability.

Objective: In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD.

Method: The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures.

Results: We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy.

Conclusions: Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates.
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http://dx.doi.org/10.3233/JHD-160226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181668PMC
December 2016

SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

Cell Chem Biol 2016 07 14;23(7):849-861. Epub 2016 Jul 14.

Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders.
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http://dx.doi.org/10.1016/j.chembiol.2016.05.015DOI Listing
July 2016

Design and Evaluation of 3-(Benzylthio)benzamide Derivatives as Potent and Selective SIRT2 Inhibitors.

ACS Med Chem Lett 2015 May 26;6(5):607-11. Epub 2015 Mar 26.

Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , Evanston, Illinois 60208-3113, United States.

Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3-(benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased α-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregation in PC12 cells.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434462PMC
May 2015

The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia.

PLoS One 2015 21;10(1):e0116919. Epub 2015 Jan 21.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America.

Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson's disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson's disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson's disease, and previously in Huntington's disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116919PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301865PMC
January 2016

Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors.

Eur J Med Chem 2014 Apr 6;76:414-26. Epub 2014 Feb 6.

Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA. Electronic address:

Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
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http://dx.doi.org/10.1016/j.ejmech.2014.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019389PMC
April 2014

The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models.

Cell Rep 2012 Dec 29;2(6):1492-7. Epub 2012 Nov 29.

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129-4404, USA.

Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson's disease and Huntington's disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.
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http://dx.doi.org/10.1016/j.celrep.2012.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534897PMC
December 2012

SIRT2 as a Therapeutic Target for Age-Related Disorders.

Front Pharmacol 2012 3;3:82. Epub 2012 May 3.

Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular Lisboa, Portugal.

Sirtuin proteins are conserved regulators of aging that have recently emerged as important modifiers of several diseases which commonly occur later in life such as cancer, diabetes, cardiovascular, and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7), which display diversity in subcellular localization and function. SIRT1 has received much of attention due to its possible impact on longevity, while important biological and therapeutic roles of other sirtuins have been underestimated and just recently recognized. Here we focus on SIRT2, a member of the sirtuin family, and discuss its role in cellular and tissue-specific functions. This review summarizes the main scientific advances on SIRT2 protein biology and explores its potential as a therapeutic target for treatment of age-related disorders.
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http://dx.doi.org/10.3389/fphar.2012.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342661PMC
October 2012

Editorial on special topic: sirtuins in metabolism, aging, and disease.

Front Pharmacol 2012 24;3:71. Epub 2012 Apr 24.

Department of Neurology, Harvard Medical School and Massachusetts General Hospital Boston, MA, USA.

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http://dx.doi.org/10.3389/fphar.2012.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334976PMC
October 2012

3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2).

Bioorg Med Chem Lett 2012 Apr 3;22(8):2789-93. Epub 2012 Mar 3.

Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States.

Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)-N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2012.02.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326608PMC
April 2012

Inhibition of Sirtuin 2 with Sulfobenzoic Acid Derivative AK1 is Non-Toxic and Potentially Neuroprotective in a Mouse Model of Frontotemporal Dementia.

Front Pharmacol 2012 12;3:42. Epub 2012 Mar 12.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School Charlestown, MA, USA.

Tauopathies including tau-associated Frontotemporal dementia (FTD) and Alzheimer's disease are characterized pathologically by the formation of tau-containing neurofibrillary aggregates and neuronal loss, which contribute to cognitive decline. There are currently no effective treatments to prevent or slow this neural systems failure. The rTg4510 mouse model, which expresses a mutant form of the tau protein associated with FTD with Parkinsonism-17, undergoes dramatic hippocampal and cortical neuronal loss making it an ideal model to study treatments for FTD-related neuronal loss. Sirtuins are a family of proteins involved in cell survival that have the potential to modulate neuronal loss in neurodegenerative disorders. Here we tested the hypothesis that sirtuin 2 (SIRT2) inhibition would be non-toxic and prevent neurodegeneration in rTg4510 brain. In this study we delivered SIRT2 inhibitor AK1 directly to the hippocampus with an osmotic minipump and confirmed that it reached the target region both with histological assessment of delivery of a dye and with a pharmacodynamic marker, ABCA1 transcription, which was upregulated with AK1 treatment. AK1 treatment was found to be safe in wild-type mice and in the rTg4510 mouse model, and further, it provided some neuroprotection in the rTg4510 hippocampal circuitry. This study provides proof-of-concept for therapeutic benefits of SIRT2 inhibitors in both tau-associated FTD and Alzheimer's disease, and suggests that development of potent, brain permeable SIRT2 inhibitors is warranted.
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http://dx.doi.org/10.3389/fphar.2012.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298895PMC
October 2012

The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS.

Hum Mol Genet 2011 Oct 26;20(20):3986-96. Epub 2011 Jul 26.

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02115, USA.

Sirtuin 2 (SIRT2) is one of seven known mammalian protein deacetylases homologous to the yeast master lifespan regulator Sir2. In recent years, the sirtuin protein deacetylases have emerged as candidate therapeutic targets for many human diseases, including metabolic and age-dependent neurological disorders. In non-neuronal cells, SIRT2 has been shown to function as a tubulin deacetylase and a key regulator of cell division and differentiation. However, the distribution and function of the SIRT2 microtubule (MT) deacetylase in differentiated, postmitotic neurons remain largely unknown. Here, we show abundant and preferential expression of specific isoforms of SIRT2 in the mammalian central nervous system and find that a previously uncharacterized form, SIRT2.3, exhibits age-dependent accumulation in the mouse brain and spinal cord. Further, our studies reveal that focal areas of endogenous SIRT2 expression correlate with reduced α-tubulin acetylation in primary mouse cortical neurons and suggest that the brain-enriched species of SIRT2 may function as the predominant MT deacetylases in mature neurons. Recent reports have demonstrated an association between impaired tubulin acetyltransferase activity and neurodegenerative disease; viewed in this light, our results showing age-dependent accumulation of the SIRT2 neuronal MT deacetylase in wild-type mice suggest a functional link between tubulin acetylation patterns and the aging brain.
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http://dx.doi.org/10.1093/hmg/ddr326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203628PMC
October 2011

A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase.

ACS Chem Biol 2011 Jun 9;6(6):540-6. Epub 2011 Mar 9.

Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Sirtuin 2 (SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of cholesterol biosynthesis in an in vitro Huntington's disease model. This study sought to identify the first brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models. Using biochemical sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and drug development, targeting metabolic dysfunctions in CNS disorders where abnormal cholesterol homeostasis is implicated.
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http://dx.doi.org/10.1021/cb100376qDOI Listing
June 2011

Huntington's disease: From molecular basis to therapeutic advances.

Int J Biochem Cell Biol 2011 Jan 4;43(1):20-4. Epub 2010 Nov 4.

Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.

Huntington's disease is an autosomal dominant genetic neurodegenerative disorder, which is characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss. The disease is caused by pathological CAG-triplet repeat extension(s), encoding polyglutamines, within the gene product, huntingtin. Huntingtin is ubiquitously expressed through the body and is a protein of uncertain molecular function(s). Mutant huntingtin, containing pathologically extended polyglutamines causes the earliest and most dramatic neuropathologic changes in the neostriatum and cerebral cortex. Extended polyglutamines confer structural conformational changes to huntingtin, which gains novel properties, resulting in aberrant interactions with multiple cellular components. The diverse and variable aberrations mediated by mutant huntingtin perturb many cellular functions essential for neuronal homeostasis and underlie pleiotropic mechanisms of Huntington's disease pathogenesis. The only approved drug for Huntington's disease is a symptomatic treatment, tetrabenazine; thus, novel neuroprotective strategies, slowing, blocking and possibly reversing disease progression, are vital for developing effective therapies.
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http://dx.doi.org/10.1016/j.biocel.2010.10.014DOI Listing
January 2011

Drug discovery for CNS disorders: from bench to bedside.

CNS Neurol Disord Drug Targets 2010 Dec;9(6):668

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http://dx.doi.org/10.2174/187152710793237395DOI Listing
December 2010

Identification of tri- and tetracyclic pyrimidinediones as sirtuin inhibitors.

ChemMedChem 2010 May;5(5):674-7

Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Italy.

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http://dx.doi.org/10.1002/cmdc.201000030DOI Listing
May 2010

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.

Proc Natl Acad Sci U S A 2010 Apr 8;107(17):7927-32. Epub 2010 Apr 8.

Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.
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http://dx.doi.org/10.1073/pnas.1002924107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867924PMC
April 2010

Histone deacetylase inhibitors and neurodegenerative disorders: holding the promise.

Curr Pharm Des 2009 ;15(34):3940-57

Pasteur Institute, Cenci-Bolognetti Foundation, Department of Drug Chemistry and Technologies, University of Rome "La Sapienza", P. le A. Moro 5, 00185 Rome, Italy.

Neurodegenerative disorders (NDs) such as Huntington's disease, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and others are multi-factorial illnesses, in which many pathways (still poorly understood) act serially and in parallel to give a determined pathologic phenotype. Thus, presently there are no effective cures for these diseases. Some phenotypic as well as mechanistic features, common to the most of NDs, can be linked to epigenetic defects, that can lead to alteration of acetylation homeostasis and impairment of the histone acetyltransferase (HAT): histone deacetylase (HDAC) balance. Here we survey most of the recent applications of HDAC inhibitors in the cited NDs, and we make the point of our (up to now) knowledge about the involvement of singular HDAC/SIRT isoform in NDs and other CNS pathologies.
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http://dx.doi.org/10.2174/138161209789649349DOI Listing
March 2010

Central role of alpha-synuclein oligomers in neurodegeneration in Parkinson disease.

Arch Neurol 2008 Dec;65(12):1577-81

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Bldg 114, 3300 16th St, Charlestown, MA 02129-4404, USA.

Selective death of nigrostriatal neurons, which leads to Parkinson disease, is explained by misfolding of brain protein alpha-synuclein. Herein, we review the data supporting this concept, propose a scheme of events leading to synuclein-induced neuronal death, and discuss protein deacetylase sirtuins as new potential therapeutic targets involved in this process.
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http://dx.doi.org/10.1001/archneur.65.12.1577DOI Listing
December 2008

Therapeutic application of histone deacetylase inhibitors for central nervous system disorders.

Nat Rev Drug Discov 2008 Oct;7(10):854-68

Harvard Medical School, Massachusetts General Hospital, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts 02129-4404, USA.

Histone deacetylases (HDACs)--enzymes that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors--which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways--have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis.
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http://dx.doi.org/10.1038/nrd2681DOI Listing
October 2008

Cellular pathways leading to neuronal dysfunction and degeneration.

Drug News Perspect 2007 Oct;20(8):501-9

Department of Neurology, Harvard Medical School, Disease, Massachusetts, USA.

There is no cure for devastating neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's diseases or amyotrophic lateral sclerosis, which cause longterm suffering and ultimately death. Slowly progressing neurodegenerative diseases affect the lives of many thousands of patients and their families. These disorders are characterized by pathological changes in disease-specific areas of the brain. In each disease, these pathological processes lead to dysfunction and degeneration in distinct subsets of neurons. Research on neurodegenerative disorders has revealed a complex picture of cellular pathology involving abnormalities in biochemical processes, gene regulation, responses to external stimuli, etc. However, despite the differences in the clinical manifestations and selective neuronal vulnerability, on cellular and molecular levels the underlying pathological processes appear similar across different diseases, suggesting common pathways of neurodegeneration. Elucidation of the precise neurodegenerative mechanism(s) is essential for development of effective and safe therapy for these lethal human disorders.
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http://dx.doi.org/10.1358/dnp.2007.20.8.1157616DOI Listing
October 2007

Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.

Science 2007 Jul 21;317(5837):516-9. Epub 2007 Jun 21.

Alzheimer's Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA.

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.
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http://dx.doi.org/10.1126/science.1143780DOI Listing
July 2007

Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators.

J Biol Chem 2007 Aug 12;282(34):24554-62. Epub 2007 Jun 12.

Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy.

Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.
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http://dx.doi.org/10.1074/jbc.M609885200DOI Listing
August 2007

Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced cytotoxicity in Parkinson's disease in vitro models.

Biochem Biophys Res Commun 2007 Jun 5;357(3):596-602. Epub 2007 Apr 5.

Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg. 114-3300, 16th St., Charlestown, MA 02129-4404, USA.

Treatments based on pharmacological inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) have been suggested for a broad variety of human disorders, including Parkinson's disease (PD). The neuroprotective effects underlying the efficacy of PARP-1 inhibitors in PD models suggest a role for PARP-1 in neurodegeneration. In this study, we assessed the efficacy of PARP-1 inhibition in two distinct PD models. First, we tested a panel of small molecule PARP-1 inhibitors in alpha-synuclein (aSyn) cytotoxicity assay, where we observed compound-dependent ameliorating effects. Next, we tested the same panel in primary ventral mesencephalic neuronal cultures, treated with MPP(+). Dopaminergic neurons, the primary cells affected in PD, were selected and subjected to analysis. A significant ameliorating effect was achieved only with a highly potent PARP-1 inhibitor. Our data implicates aberrant PARP-1 function in different pathways of neurodegeneration. Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients.
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http://dx.doi.org/10.1016/j.bbrc.2007.03.163DOI Listing
June 2007

Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragments.

J Biomol Screen 2007 Apr 22;12(3):351-60. Epub 2007 Mar 22.

Massachusetts Institute of Technology, Cambridge, MA, USA.

CAG-triplet repeat extension, translated into polyglutamines within the coding frame of otherwise unrelated gene products, causes 9 incurable neurodegenerative disorders, including Huntington's disease. Although an expansion in the CAG repeat length is the autosomal dominant mutation that causes the fully penetrant neurological phenotypes, the repeat length is inversely correlated with the age of onset. The precise molecular mechanism(s) of neurodegeneration remains elusive, but compelling evidence implicates the protein or its proteolytic fragments as the cause for the gain of novel pathological function(s). The authors sought to identify small molecules that target the selective clearance of polypeptides containing pathological polyglutamine extension. In a high-throughput chemical screen, they identified compounds that facilitate the clearance of a small huntingtin fragment with extended polyglutamines fused to green fluorescent protein reporter. Identified hits were validated in dose-response and toxicity tests. Compounds have been further tested in an assay for clearance of a larger huntingtin fragment, containing either pathological or normal polyglutamine repeats. In this assay, the authors identified compounds selectively targeting the clearance of mutant but not normal huntingtin fragments. These compounds were subjected to a functional assay, which yielded a lead compound that rescues cells from induced mutant polyglutamine toxicity.
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http://dx.doi.org/10.1177/1087057107299428DOI Listing
April 2007

Drug targeting of dysregulated transcription in Huntington's disease.

Prog Neurobiol 2007 Nov 23;83(4):249-59. Epub 2007 Feb 23.

Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129-4404, USA.

Transcriptional dysregulation in Huntington's disease (HD) is a well documented and broadly studied phenomenon. Its basis appears to be in huntingtin's aberrant protein-protein interactions with a variety of transcription factors. The development of therapeutics targeting altered transcription, however, faces serious challenges. No single transcriptional regulator has emerged as a primary actor in HD. The levels of literally hundreds of RNA transcripts are altered in affected cells and it is uncertain which are most relevant. The protein-protein interactions of mutant huntingtin with transcriptional factors do not constitute conventional and easy targets for drug molecules. Nevertheless, potential therapeutic advances, targeting transcriptional deregulation in HD, have been made in recent years. In this chapter we review current progress in this area of therapeutic development. We also discuss possible drug discovery strategies targeting altered transcriptional pathways.
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http://dx.doi.org/10.1016/j.pneurobio.2007.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2110959PMC
November 2007