Proteomics as a Tool for Discovery:  Proteins Implicated in Alzheimer's Disease are Highly Expressed in Normal Pancreatic Islets

Nicolls, Mark R.; D’Antonio, Jason M.; Hutton, John C.; Gill, Ronald G.; Czwornog, Jennifer; Duncan, Mark W.

doi:10.1021/pr025576x

Cited by 56 publications

(50 citation statements)

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“…This approach successfully filters out highly expressed genes in contaminating cell types (e.g., SST, GCG from somatostatin, and glucagon cells contaminating the beta cell population), otherwise mistaken as key players in the expression signature of beta cells. In addition to known beta-cell-specific transcripts (INS, IGF2, PDX1) we highlight further targets, some featured already in a microarray analysis of sorted islet cells (Dorrell et al 2011b), e.g., RGS16, negative regulator of G-protein signaling, involved in endocrine pancreas development and re-expressed in adult cells in response to GLP-1 (Villasenor et al 2010); ADCYAP1, pituitary adenylate cyclase activating polypeptide 1, involved in insulin secretion and beta cell regeneration/proliferation (Sakurai et al 2011); HADH, hydroxyacyl-CoA dehydrogenase, negative regulator of insulin secretion (Hardy et al 2007) associated with Alzheimer's (Nicolls et al 2003), which is in turn associated with diabetes. Many other genes however have not been described before in the context of beta cells, including: NPTX2, neuronal pentraxin 2, found in neuronal cells and gliomas but also shown to be frequently downregulated in pancreatic cancers (Zhang et al 2012); TSPAN1, tetraspanin 1, which can associate with alpha6.beta1 integrin and promote FAK phosphorylation (Huang et al 2008) shown by us to be involved in insulin secretion (Rondas et al 2011); GPM6A, neuronal membrane glycoprotein of unknown function but identified as a beta cell marker in sorted mouse islet cells (Dorrell et al 2011a); BMP5, bone morphogenic protein 5, implicated in pancreas and fetal beta cell development ( Jiang et al 2002); and P2RY1, purinergic receptor through which ADP and ATP modulate insulin secretion (Fernandez-Alvarez et al 2001).…”

Section: à7mentioning

confidence: 99%

Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

et al. 2013

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SwitzerlandElucidating the pathophysiology and molecular attributes of common disorders as well as developing targeted and effective treatments hinges on the study of the relevant cell type and tissues. Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. We perform the first comparison of gene expression profiles between beta cells, whole islets, and beta cell depleted islet preparations, revealing thus beta-cell-specific expression and splicing signatures. Further, we demonstrate that genes with consistent increased expression in beta cells have neuronal-like properties, a signal previously hypothesized. Finally, we find evidence for extensive allelic imbalance in expression and uncover genetic regulatory variants (eQTLs) active in beta cells. This first molecular blueprint of the human beta cell offers biological insight into its differentiated function, including expression of key genes associated with both major types of diabetes.

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Section: à7mentioning

confidence: 99%

Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

et al. 2013

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“…Increased oxidation was observed for chaperonin subunit 5 and mortalin in an ApoE-knockout mouse model for AD [108]. Several heat shock proteins with deranged levels in AD, calreticulin, DnaK, GRP78, HSP70, and TCP-1, were found to be up-regulated in normal pancreatic islets [93].…”

Section: Heat Shock Proteinsmentioning

confidence: 98%

“…In CJD, peroxiredoxin 1 showed decreased and peroxiredoxin 6 increased levels [92]. Peroxiredoxins like several other proteins implicated in AD were found to be highly expressed in normal pancreatic islets [93]. Proteomic analysis of the brain of a gracile axonal dystrophy mouse model with dysfunctional ubiquitin C-terminal hydrolase L-1 revealed increased oxidation for peroxiredoxin (thioredoxin peroxidase) and several other proteins [94].…”

Section: Animal Modelmentioning

confidence: 99%

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Proteomics‐driven progress in neurodegeneration research

Fountoulakis

Κοσσίδα

2006

Electrophoresis

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Proteomics-driven progress in neurodegeneration researchProteomics technologies have been widely used in the investigation of neurodegenerative and psychiatric disorders, and in particular in the detection of differences between healthy individuals and patients suffering from such diseases. Thus, brain and cerebrospinal fluid (CSF) samples from patients with Alzheimer's disease, Down syndrome, Pick's disease, Parkinson's disease, schizophrenia, and other disorders as well as brain and CSF from animals serving as models of neurological disorders have been analyzed by proteomics. 2-DE followed by MALDI-TOF-MS has been mainly applied as this proteomics approach provides the possibility of convenient quantification of protein levels and detection of post-translational modifications. About 330 unique proteins with deranged levels and modifications have been detected by proteomics approaches to be related to neurodegeneration and psychiatric disorders. They are mainly involved in metabolism pathways, cytoskeleton formation, signal transduction, guidance, detoxification, transport, and conformational changes. In this article, we provide a summary of the major contributions of proteomics technologies in the study of neurodegenerative and psychiatric diseases, in particular, in the detection of changes in protein levels and modifications related to these disorders. IntroductionNeurodegeneration is a major hallmark of a series of genetic and acquired disorders of the central nervous system (CNS), like Alzheimer's disease (AD), Down syndrome (DS), Pick's disease, Creutzfeldt-Jakob disease (CJD), and Parkinson's disease, which result in severe cognitive and motor deficits. A common characteristic of these diseases is that they are multifactorial.Their molecular basis is unknown and individual biomarkers are not reliable. Genomics and proteomics approaches have been applied to obtain a better understanding of neurodegeneration and psychiatric disorders. Genomics has been used to map and identify genes that are mutated in a wide variety of such disorders, like presenilins in AD. Next to genomics, which only provides a partial view of the biological problem, proteomics is widely used in clinical diagnosis as well and many changes in protein levels associated with specific diseases have been identified [1,2].Proteomics is a technology-driven science that studies the proteins of the various biological systems, their structures, interactions, post-translational modifications, and in particular the changes in their levels and modifications, which are the result of specific diseases or are induced by external factors.

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“…This reference map can be useful for scientists using similar 2DE protocols for comparison of their images. Following two more recent studies, 76 new protein identities were added to this first reference map [99,100]. The latter study demonstrated that many proteins implicated in Alzheimer's disease are highly expressed in normal pancreatic islets.…”

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confidence: 99%

Type 1 diabetes: entering the proteomic era

D’Hertog¹,

Mathieu²,

Overbergh³

2006

Expert Review of Proteomics

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During the last decade, a major breakthrough in the field of proteomics has been achieved. This review describes available techniques for proteomic analyses, both gel and non-gel based, particularly concentrating on relative quantification techniques. The principle of the different techniques is discussed, highlighting the advantages and drawbacks of recently available visualization methods in gel-based assays. In addition, recent developments for quantitative analysis in non-gel-based approaches are summarized. This review focuses on applications in Type 1 diabetes. These mainly include proteomic studies on pancreatic islets in animal models and in the human situation. Also discussed are mass spectrometry-based studies on T-cells, and studies on the development of diagnostic markers for diabetic nephropathology by capillary electrophoresis coupled to mass spectrometry. Expert Rev. Proteomics 3(2), 223-236 (2006) From genomics to proteomicsThe term proteome was first introduced in 1994 by Wilkins and coworkers in Siena, Italy [1]. Proteome refers to the already established terms genome and transcriptome, and describes all proteins present in a given cell or organism. Although researchers realized that a systematic analysis of the proteins expressed by a cell or organism would be essential to understand the mechanisms and pathways involved in all aspects of cell growth and differentiation many years earlier, it was only until the completion of the first genome projects that this proteome investigation boosted enormously. This was the start of the post-genomic era, where researchers realized that many processes occur in a cell from the transition from genome to proteome, which could not be explained solely by genomics and transcriptomics.It is undoubtedly clear that the availability of the human genome has aided greatly to our understanding of many genetic disorders and is a great step forward in the diagnosis and treatment possibilities for their associated diseases. However, the majority of diseases, even if they are genetic, are not caused by a single mutation. Rather, they are a combinatorial effect of multiple genetic mutations or an unfavorable combination of common alleles. In addition, environmental factors may also contribute to initiation of the disease, which is true for Type 1 diabetes (T1D). Concurrently with the sequencing of the human genome, RNA-based assays, such as microarrays and the real-time reverse transcriptase PCR technique, were a major research topic, both in fundamental research and in clinical diagnostics [2]. Although our knowledge of the pathways involved in many diseases greatly improved, no information whatsoever could be obtained from these RNA-based studies regarding the importance of translational regulation and the role of post-translational modifications (PTMs). Moreover, some authors proved a very poor correlation between mRNA levels and protein levels [3,4]. From this perspective, proteomics covers the real executing molecules that change expression in a diseased state or aft...

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Proteomics as a Tool for Discovery: Proteins Implicated in Alzheimer's Disease are Highly Expressed in Normal Pancreatic Islets

Cited by 56 publications

References 56 publications

Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

Proteomics‐driven progress in neurodegeneration research

Type 1 diabetes: entering the proteomic era

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