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Sirtuins in neurodegenerative diseases: a biological-chemical perspective.

ABSTRACT: Sirtuins, commonly known as NAD(+)-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a number of studies have unequivocally supported the idea of sirtuins having therapeutic potential in neurodegenerative diseases such as stroke, ischemic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. To exploit the therapeutic potential of sirtuins, their manipulation in terms of development of small-molecule modulators, inhibitors and analogs has increased dramatically since their inception, in both scientific and industrial worlds. Studies on the structure and catalytic core of sirtuins along with chemical mechanisms and substrate specificity have provided important input into the design and synthesis of sirtuin modulators. To study the role of sirtuins in the biological system, it has become extremely important to understand the molecular and chemical structure of sirtuins. In this review, we have discussed the biological role of sirtuins in various neurodegenerative diseases, and also provided an insight into their chemical structure.

SUBMITTER: Raghavan A

PROVIDER: S-EPMC3254029 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Sirtuins in neurodegenerative diseases: a biological-chemical perspective.

Raghavan Aparna A Shah Zahoor A ZA

Neuro-degenerative diseases 20111028 1

Sirtuins, commonly known as NAD(+)-dependent class III histone deacetylase enzymes, have been extensively studied to evaluate their potential role in different disease states. Based on the published literature, sirtuins have been implicated in providing a myriad of intrinsic and extrinsic biological effects, which in turn may play an important role in the treatment of various disorders such as type II diabetes, obesity, cancer, aging and different neurodegenerative diseases. In particular, a num ...[more]

PMID: 22041967

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Project description:Background: For measuring the impact in clinical and scientific research, the citation count of the articles is used in the bibliometric analysis, although there is no comprehensive summary of neurodegenerative disease research. This study intends to provide the neuroscientists and investigators with a practical reference guide to appraise the most important and influential articles written on this subject through a macroscopic view of the research activities on neurodegenerative diseases. Materials and Methods: The Clarivate Analytics Web of Science was searched in July 2020. To ensure the breadth of the search scope, the search terms were confirmed as "multiple sclerosis" (MS) or "amyotrophic lateral sclerosis" (ALS) or "Parkinson's" or "Alzheimer's" or "Huntington's" or "neurodegenerative." After excluding completely unrelated articles, the top-cited articles were collected and evaluated from special characteristics. The data analysis was performed using SPSS 18.0. The articles were characterized by citation number, publication year, topic, study type, authorship, journal, country, and institute of responding author and foundation. Results: The query identified 593,050 articles. A total of 45% of the top-cited articles were published during 2000-2009, followed by 30 articles from 1990-1999. Diagnosis and pathology were the main research categories (n = 62). Alzheimer's disease (AD) was the main study topic (n = 43). Meanwhile, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Notably, 69 of 100 articles were studied in the United States, and the National Institutes of Health sponsored 49 articles. There were only 22 articles that can be divided by evidence level. No article was categorized as level 1 evidence. In the journal list with multiple articles, seven of 15 were general journals. The 58 authors, who contributed to more than one article, have been identified by VOSviewer, and the clusters of authors reveal the evolution of research focus in neurodegenerative diseases. Conclusions: This study analyzed the bibliometric characteristics and connections of 100 top-cited articles in the field of neurodegenerative diseases in the Web of Science. Their main outcomes were as follows: First, the pathology and diagnostic researches took a major role in top-cited articles while the therapy articles are relatively less. Second, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Third, researchers also submitted their researches to general journals, not just focused on specialty journals.

Project description:Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions. A total of 113 cases were selected retrospectively on the basis of a confirmed clinical and neuropathological diagnosis and snap-frozen brain blocks were provided by various tissue banks within the BrainNet Europe network. Total RNA was extracted from dissected snap-frozen tissue (< 100 mg) by the individual laboratories according to a BNE optimised common protocol using the RNeasy(r) tissue lipid mini kit (Qiagen Ltd, Crawley, UK) according to the manufacturer's instructions, and was stored at -80C until further use. Gene expression analysis was performed on the RNA samples using the Illumina whole genome HumanRef8 v2 BeadChip (Illumina, London, UK). All the labelling and hybridisation of the samples was carried out in a single experiment by the Imperial College group to reduce the technical variability. RNA samples were prepared for array analysis using the Illumina TotalPrep(tm)-96 RNA Amplification Kit (Ambion/Applied Biosystems, Warrington, UK). Finally, the BeadChips we re scanned using the Illumina BeadArray Reader. The data was extracted using BeadStudio 3.2 (Illumina). Data normalisation and gene differential expression analyses were conducted using the Rosetta error models available in the Rosetta Resolver(r) system (Rosetta Biosoftware, Seattle, Wa, USA). Two samples presented very low signal expression most likely due to hybridization problems and did not pass the quality control test. They are not represented here. One of the 2 samples was a replicate, therefore there was loss of only 1 case bringing the grand total of cases used to 112 (total of samples of 118 including 6 replicates).

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Sirtuins in neurodegenerative diseases: a biological-chemical perspective.

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Sirtuins in neurodegenerative diseases: a biological-chemical perspective.

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