The Potential of Proteomics in Understanding Neurodegeneration

Pal, Ramavati; Larsen, Jan Petter; Møller, Simon Geir

doi:10.1016/bs.irn.2015.05.002

Cited by 15 publications

(9 citation statements)

References 169 publications

(132 reference statements)

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“…In this regard, the question of possible reasons of fatal fails of late stages of AD drugs clinical trials are actively discussed in numerous reviews and research articles . One possible reason might be linked to the heterogeneous nature of AD pathology . These considerations had led to a paradoxical conclusion that larger clinical trials containing more diverse patient population are not always better.…”

Section: Discussionmentioning

confidence: 99%

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Бачурин

Bovina

Ustyugov

2017

Medicinal Research Reviews

255

155

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Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.

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Section: Discussionmentioning

confidence: 99%

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Бачурин

Bovina

Ustyugov

2017

Medicinal Research Reviews

255

155

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“…Одна из возможных причин неудач может быть связана с гетерогенностью патологии БА [208,209]. Эти соображения привели к парадоксальному выводу, что развёрнутые клинические исследования, содержащие разнородную популяцию пациентов, не всегда приводят к успеху.…”

Section: репозиционирование известных ранее лекарственных препаратовunclassified

Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

Бачурин

Bovina

Ustyugov

2018

BMCRM

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Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites www.clinicaltrials.gov and Alzforum.org as well as the Thomson Reuters «Integrity» database. We revealed three major trends in AD drug discovery. First, developing of “disease-modifying agents” could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.

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“…Proteomics is a powerful methodology to investigate how protein expression is affected in the pathogenesis of a disease process, providing a complement to the information obtained by functional genomics. Such unbiased approaches permit the identification of novel protein changes and are used to study various illnesses[ 10 , 11 ]. Quantitative proteomics can be performed using three methods: label-free quantification, metabolic labeling with stable isotope labeling by amino acids in cell culture, and stable-isotope labeling using chemical reagents covalently attached in vitro such as dimethyl-labeling, tandem mass tags (TMTs), and isobaric tags for relative and absolute quantification (iTRAQ)[ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Such unbiased approaches permit the identification of novel protein changes and are used to study various illnesses[ 10 , 11 ]. Quantitative proteomics can be performed using three methods: label-free quantification, metabolic labeling with stable isotope labeling by amino acids in cell culture, and stable-isotope labeling using chemical reagents covalently attached in vitro such as dimethyl-labeling, tandem mass tags (TMTs), and isobaric tags for relative and absolute quantification (iTRAQ)[ 10 , 11 ]. Notably, the use of isobaric tag-based TMTs and iTRAQ produces high-quality data with high sensitivity, excellent signal-to-noise ratios, and a broad dynamic range.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l

et al. 2017

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α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called synucleinopathies, which are characterized by the intracellular presence of aggregated α-synuclein. However, the mechanism of α-synuclein biology in synucleinopathies pathogenesis is not fully understood. In this study, mice overexpressing human A30P*A53T α-synuclein were evaluated by a motor behavior test and count of TH-positive neurons, and then two-dimensional liquid chromatography-tandem mass spectrometry coupled with tandem mass tags (TMTs) labeling was employed to quantitatively identify the differentially expressed proteins of substantia nigra pars compacta (SNpc) tissue samples that were obtained from the α-synuclein transgenic mice and wild type controls. The number of SNpc dopaminergic neurons and the motor behavior were unchanged in A30P*A53T transgenic mice at the age of 6 months. Of the 4,715 proteins identified by proteomic techniques, 271 were differentially expressed, including 249 upregulated and 22 downregulated proteins. These alterations were primarily associated with mitochondrial dysfunction, oxidative stress, ubiquitin-proteasome system impairment, and endoplasmic reticulum (ER) stress. Some obviously changed proteins, which were validated by western blotting and immunofluorescence staining, including Sel1l and Sdhc, may be involved in the α-synuclein pathologies of synucleinopathies. A biological pathway analysis of common related proteins showed that the proteins were linked to a total of 31 KEGG pathways. Our findings suggest that these identified proteins may serve as novel therapeutic targets for synucleinopathies.

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The Potential of Proteomics in Understanding Neurodegeneration

Cited by 15 publications

References 169 publications

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l

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