New Age of Neuroproteomics in Alzheimer’s Disease Research

Kováčech, Branislav; Žilka, Norbert; Novák, Michal

doi:10.1007/s10571-009-9358-6

Cited by 22 publications

(14 citation statements)

References 60 publications

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“…To determine the consequences of tau pathology, both in animal models and human disease, we and others have applied the tools of functional genomics [4]. Proteomic analysis, e.g., revealed separate and synergistic modes of Aβ and tau on mitochondrial functions [5], [6] while in a transcriptomic study, we identified the detoxifying enzyme glyoxalase I as a target of tau toxicity [7].…”

Section: Introductionmentioning

confidence: 99%

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Dramiga

Schütz

et al. 2012

PLoS ONE

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Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

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Section: Introductionmentioning

confidence: 99%

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Dramiga

Schütz

et al. 2012

PLoS ONE

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“…Most cases of Alzheimer disease are sporadic and idiopathic; however, mutations in three genes, APP, presenilin 1 and presenilin 2 have been identified as being responsible for a small fraction of early-onset Alzheimer disease, that accounts for approximately 5% of all Alzheimer disease cases. With increasing life-span and in the absence of interventions to slow or arrest progression of AD, the number of elderly people at risk of developing dementia is growing rapidly [11]. Large number of studies proposed various hypotheses to explain the pathogenesis or progression of sporadic AD that include the amyloid hypothesis, the oxidative stress hypothesis and APOE genotype among others [12–17].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects

Domenico

Sultana

Barone

et al. 2011

Journal of Proteomics

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Phosphorylation on tyrosine, threonine and serine residues represents one of the most important post-translational modifications and is a key regulator of cellular signaling of multiple biological processes that require a strict control by protein kinases and protein phosphatases. Abnormal protein phosphorylation has been associated with several human diseases including Alzheimer disease (AD). One of the characteristic hallmarks of AD is the presence of neurofibrillary tangles, composed of microtubule-associated, abnormally hyperphosphorylated tau protein. However, several others proteins showed altered phosphorylation levels in AD suggesting that deregulated phosphorylation may contribute to AD pathogenesis. Phosphoproteomics has recently gained attention as a valuable approach to analyze protein phosphorylation, both in a quantitave and a qualitative way. We used the fluorescent phosphospecific Pro-Q Diamond dye to identify proteins that showed alterations in their overall phosphorylation in the hippocampus of AD vs. control (CTR) subjects. Significant changes were found for 17 proteins involved in crucial neuronal process such as energy metabolism or signal transduction. These phosphoproteome data may provide new clues to better understand molecular pathways that are deregulated in the pathogenesis and progression of AD.

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“…Other processes, such as oxidative damage to DNA and RNA, have also been implicated in the pathogenesis of AD [11], as well as lesion histogenesis [12–15]. Still others suggest tau protein metabolism as the rate-limiting factor in disease, specifically phosphorylation, conformational changes and cleavage [16–21]. A number of other mechanisms have been implicated, including such general mechanisms as apoptosis, inflammation and excitotoxicity.…”

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confidence: 99%

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Mondragón‐Rodríguez

Basurto-Islas

Lee

et al. 2010

Expert Review of Neurotherapeutics

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Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed. KeywordsAlzheimer's disease; amyloid; fibrillary deposits; oxidative stress; tau Amyloid plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of the progression of Alzheimer's disease (AD). The questions of how, why and when they appear are, therefore, pertinent to understanding the disorder and, as a result, research efforts into the relationship between lesion and pathogenesis have been substantial. It is now known that specific molecular events are associated with the development of AD, although their exact relationship to lesion appearance is still controversial. Pathogenic mutations leading, for example, to amyloid-β (Aβ) deposition, are a primary piece of evidence [1][2][3], while a wide range of other metabolic abnormalities have been proposed [4][5][6][7][8]. During early AD stages, cell cycle deregulation has been related to the disease [9,10], which may also contribute to the protein aggregates. Other processes, such as oxidative damage to DNA and RNA, have † Author for correspondence: Tel.: +1 216 368 3670 Fax: +1 216 368 8964 mark.smith@case.edu.For reprint orders, please contact reprints@expert-reviews.com Financial & competing interests disclosureThis work was funded by NIH grant AG026151. Mark A Smith is, or has in the past been, a paid consultant for, owns equity or stock options in and/or receives grant funding from Anavex, Canopus BioPharma, Medivation, Neurotez, Neuropharm, Panacea Pharmaceuticals and Voyager Pharmaceuticals. George Perry is, or has in the past been, a paid consultant for and/or owns equity or stock options in Neurotez Pharmaceuticals, Panacea Pharmaceuticals, Takeda Pharmaceuticals and Voyager Pharmaceuticals. Xiongwei Zhu is a paid Advisory Board member for Medivation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Genetic events: causative, but how? NIH Public AccessPathogenic mutations leading to familial autosomal-dominant AD involve the Aβ precursor protein (APP) gene [22,23], and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes [24]. Apolipoprotein E (APOE) polymorphisms, sometimes referred to as familial late-onset AD, are not mutations per se, but are a significant predisposing factor [25,26]. In particular, the APOE gene has three isoforms (ε2,...

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New Age of Neuroproteomics in Alzheimer’s Disease Research

Cited by 22 publications

References 60 publications

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

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