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Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling.

ABSTRACT: Dementia is a syndrome associated with a wide range of clinical features including progressive cognitive decline and patient inability to self-care. Due to rapidly increasing prevalence in aging society, dementia now confers a major economic, social, and healthcare burden throughout the world, and has therefore been identified as a public health priority by the World Health Organization. Previous studies have established dementia as a 'proteinopathy' caused by detrimental changes in brain protein structure and function that promote misfolding, aggregation, and deposition as insoluble amyloid plaques. Despite clear evidence that pathological cognitive decline is associated with degenerative protein modifications (DPMs) arising from spontaneous chemical modifications to amino acid side chains, the molecular mechanisms that promote brain DPMs formation remain poorly understood. However, the technical challenges associated with DPM analysis have recently become tractable due to powerful new proteomic techniques that facilitate detailed analysis of brain tissue damage over time. Recent studies have identified that neurodegenerative diseases are associated with the dysregulation of critical repair enzymes, as well as the misfolding, aggregation and accumulation of modified brain proteins. Future studies will further elucidate the mechanisms underlying dementia pathogenesis via the quantitative profiling of the human brain proteome and associated DPMs in distinct phases and subtypes of disease. This review summarizes recent developments in quantitative proteomic technologies, describes how these techniques have been applied to the study of dementia-linked changes in brain protein structure and function, and briefly outlines how these findings might be translated into novel clinical applications for dementia patients. In this review, only spontaneous protein modifications such as deamidation, oxidation, nitration glycation and carbamylation are reviewed and discussed.

SUBMITTER: Adav SS

PROVIDER: S-EPMC5094070 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling.

Adav Sunil S SS Sze Siu Kwan SK Sze Siu Kwan SK

Molecular brain 20161103 1

Dementia is a syndrome associated with a wide range of clinical features including progressive cognitive decline and patient inability to self-care. Due to rapidly increasing prevalence in aging society, dementia now confers a major economic, social, and healthcare burden throughout the world, and has therefore been identified as a public health priority by the World Health Organization. Previous studies have established dementia as a 'proteinopathy' caused by detrimental changes in brain protei ...[more]

PMID: 27809929

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Project description:Brain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer's disease with cerebrovascular disease (AD + CVD) is the most prevalent form of dementia in the elder population. Thus, understanding the role(s) of brain DPMs in this dementia subtype may provide novel insight on the disease pathogenesis and may aid on the development of novel diagnostic and therapeutic tools. Two essential DPMs known to promote inflammation in several human diseases are the ureido DPMs (uDPMs) arginine citrullination and lysine carbamylation, although they have distinct enzymatic and non-enzymatic origins, respectively. Nevertheless, the implication of uDPMs in the neuropathology of dementia remains poorly understood.In this study, we use the state-of-the-art, ultracentrifugation-electrostatic repulsion hydrophilic interaction chromatography (UC-ERLIC)-coupled mass spectrometry technology to undertake a comparative characterization of uDPMs in the soluble and particulate postmortem brain fractions of subjects diagnosed with AD + CVD and age-matched controls.An increase in the formation of uDPMs was observed in all the profiled AD + CVD brains. Citrulline-containing proteins were found more abundant in the soluble fraction of AD + CVD whereas homocitrulline-containing proteins were preferentially abundant in the particulate fraction of AD + CVD brains. Several dementia-specific citrulline residues were also identified in soluble proteins previously categorized as pro-immunogenic, which include the receptor P2X7, alpha-internexin, GFAP, CNP, MBP, and histones. Similarly, diverse dementia-specific homocitrulline residues were also observed in the particulate fractions of AD + CVD in proteins that have been vastly implicated in neuropathology. Intriguingly, we also found that the amino acids immediately flanking arginine residues may specifically influence the increase in protein citrullination.Taken together, these results indicate that uDPMs widely contribute to the pathophysiology of AD + CVD by promoting neuroinflammation and proteinopathy. Furthermore, the obtained results could help to identify disease-associated proteins that can act as potential targets for therapeutic intervention or as novel biomarkers of specific neuropathology.

Project description:Parkinson's disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer's disease-type pathology. Whilst immune activation is well-described in Parkinson's disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling.

Publications

Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling.

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