Deimination in Alzheimer’s Disease

Ishigami, Akihito; Choi, Eun‐Kyoung; Kim, Yong‐Sun; Maruyama, Naoki

doi:10.1007/978-1-4614-8317-5_13

Cited by 3 publications

(5 citation statements)

References 69 publications

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“…The evidence for critical roles of PADs in various neurodegenerative diseases is mounting [ 178 , 179 , 180 , 181 , 182 , 183 ]. A human RNA-Seq transcriptome and splicing database of glia, neurones, and vascular cells of the cerebral cortex shows highest levels of PADI2 in mature astrocytes, oligodendrocytes, and microglia [ 184 ].…”

Section: Pads and Protein Deimination In Neurodegenerative Diseasementioning

confidence: 99%

“…In many cases where protein deimination has been associated with neurodegenerative diseases, including multiple sclerosis (MS) [ 185 , 186 , 187 , 188 ], AD, and PD, studies have mainly focused on histological analysis of post mortem human samples. AD post mortem human brain samples display increased protein deimination [ 179 , 180 , 181 , 189 , 190 , 191 ] and deiminated proteins are present in amyloid-containing areas in amyloid-precursor-protein/presenilin1 (APP + PSEN1) transgenic AD mouse models [ 44 , 192 ].…”

Section: Pads and Protein Deimination In Neurodegenerative Diseasementioning

confidence: 99%

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Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Lange

Gallagher

Kholia

et al. 2017

IJMS

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Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for manipulating their release from cells have recently been highlighted. One of the pathways involved in EMV shedding is driven by peptidylarginine deiminase (PAD) mediated post-translational protein deimination, which is calcium-dependent and affects cytoskeletal rearrangement amongst other things. Increased PAD expression is observed in various cancers and neurodegeneration and may contribute to increased EMV shedding and disease progression. Here, we review the roles of PADs and EMVs in cancer and neurodegeneration.

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Section: Pads and Protein Deimination In Neurodegenerative Diseasementioning

confidence: 99%

Section: Pads and Protein Deimination In Neurodegenerative Diseasementioning

confidence: 99%

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Lange

Gallagher

Kholia

et al. 2017

IJMS

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“…It was suggested that citrullination promotes the disassembly process of these intermediate filament proteins [3]. Normally, PAD2 is inactive during neurodegeneration or brain injury when the intracellular calcium balance is disturbed [214]. Experimentally, it was found that the levels of PAD2 in the hippocampus of rats are threefold higher than in the brain cortex.…”

Section: Pathological Conditions Of Citrullinationmentioning

confidence: 99%

“…Interestingly, extracted hippocampal tissues from AD and normal brain revealed that the amount of PAD2 in AD tissue was distinctly higher. In addition, histochemical examination of AD hippocampus revealed the presence of citrullinated proteins obviously in the dentate gyrus and stratum radiatum of CA1 and CA2 areas, while in the normal hippocampus tissue there were no measurable citrullinated proteins [214]. It has been identified that the citrullination of GFAP and vimentin led to their disassembling and unfolding and which subsequently changed the size and shape of astrocytes [199, 215, 216].…”

Section: Pathological Conditions Of Citrullinationmentioning

confidence: 99%

An Overview of the Intrinsic Role of Citrullination in Autoimmune Disorders

Alghamdi

Alasmari

Assiri

et al. 2019

Journal of Immunology Research

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A protein undergoes many types of posttranslation modification. Citrullination is one of these modifications, where an arginine amino acid is converted to a citrulline amino acid. This process depends on catalytic enzymes such as peptidylarginine deiminase enzymes (PADs). This modification leads to a charge shift, which affects the protein structure, protein-protein interactions, and hydrogen bond formation, and it may cause protein denaturation. The irreversible citrullination reaction is not limited to a specific protein, cell, or tissue. It can target a wide range of proteins in the cell membrane, cytoplasm, nucleus, and mitochondria. Citrullination is a normal reaction during cell death. Apoptosis is normally accompanied with a clearance process via scavenger cells. A defect in the clearance system either in terms of efficiency or capacity may occur due to massive cell death, which may result in the accumulation and leakage of PAD enzymes and the citrullinated peptide from the necrotized cell which could be recognized by the immune system, where the immunological tolerance will be avoided and the autoimmune disorders will be subsequently triggered. The induction of autoimmune responses, autoantibody production, and cytokines involved in the major autoimmune diseases will be discussed.

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“…Although the role of protein inclusions appears mainly to be protective [ 23 ], chronic accumulation of these structures in the brain is likely to threaten neuronal function and viability [ 26 ]. Within the central nervous system (CNS), several DPMs have been associated with the formation and accumulation of amyloids [ 5 ] and some studies have suggested an association between citrullination, proteinopathy [ 27 , 28 ], and brain vascular dysfunction [ 29 , 30 ]. However, despite the implication that uDPMs might be involved in the neuropathology of AD + CVD, the extent of uDPMs in affected brain cells is unknown and the role(s) of citrullination and carbamylation in the neuropathology of dementia remain far to be fully elucidated [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Brain ureido degenerative protein modifications are associated with neuroinflammation and proteinopathy in Alzheimer’s disease with cerebrovascular disease

Gallart‐Palau

Serra

Lee

et al. 2017

J Neuroinflammation

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BackgroundBrain 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.MethodsIn 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.ResultsAn 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.ConclusionsTaken 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0946-y) contains supplementary material, which is available to authorized users.

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Deimination in Alzheimer’s Disease

Cited by 3 publications

References 69 publications

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

An Overview of the Intrinsic Role of Citrullination in Autoimmune Disorders

Brain ureido degenerative protein modifications are associated with neuroinflammation and proteinopathy in Alzheimer’s disease with cerebrovascular disease

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