Protein Deimination in Protein Misfolding Disorders: Modeled in Human Induced Pluripotent Stem Cells (iPSCs)

Lange, Sigrun; Wray, Selina; Devine, Michael J.; Matarı́n, Mar; Hardy, John

doi:10.1007/978-3-319-58244-3_13

Cited by 7 publications

(20 citation statements)

References 54 publications

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“…We also observed similar changes in pan-protein and histone H3 deimination in iPSC derived neurones from patients carrying α-synuclein triplication [39] compared to control neurones [36]. The predominantly expressed isozyme observed was PAD4 while PAD2 was also expressed, albeit at lower levels [36]. Evidence for increased PAD expression with progression of neurodegenerative disease was obtained by analysis of whole genome microarrays from mouse models carrying TAU and APP+PSEN1 mutations.…”

Section: Protein Deimination In Neurodegenerative Diseasessupporting

confidence: 60%

“…Previous studies on in vivo models of CNS damage showed that PAD-upregulation and increased protein deimination lead to vast neuronal death which was preventable by pharmacological PAD inhibition, significantly reducing neuroinflammatory responses and histone H3 deimination, which has implications in gene regulation [23,[33][34][35]. In addition we have observed increased PAD expression during disease progression in tau mutation mouse models compared to age-matched controls [36]. Using iPSC neuronal models derived from fibroblasts from patients carrying neurodegenerative valosin containing protein VCPR155C and VCPR191Q mutations [37,38], as well as from patients carrying α-synuclein triplication [39] we have also observed significantly increased pan-protein deimination compared to control (non-mutation carrying) cultures, with significant changes in histone H3 deimination [36].…”

Section: Introductionmentioning

confidence: 53%

“…In addition we have observed increased PAD expression during disease progression in tau mutation mouse models compared to age-matched controls [36]. Using iPSC neuronal models derived from fibroblasts from patients carrying neurodegenerative valosin containing protein VCPR155C and VCPR191Q mutations [37,38], as well as from patients carrying α-synuclein triplication [39] we have also observed significantly increased pan-protein deimination compared to control (non-mutation carrying) cultures, with significant changes in histone H3 deimination [36]. These studies are in accordance with the mounting evidence for significant roles for protein deimination in neurodegenerative diseases [40][41][42][43][44][45].…”

Section: Introductionmentioning

confidence: 67%

“…In pilot studies, using iPSC neuronal models derived from fibroblasts from patients [37] carrying valosin-protein containing mutations VCPR155C and VCPR191Q we have observed significantly increased pan-protein deimination compared to control (non-mutation carrying) neurones, with significant increases in histone H3 deimination in VCPR155C carrying neurones [36]. We also observed similar changes in pan-protein and histone H3 deimination in iPSC derived neurones from patients carrying α-synuclein triplication [39] compared to control neurones [36]. The predominantly expressed isozyme observed was PAD4 while PAD2 was also expressed, albeit at lower levels [36].…”

Section: Protein Deimination In Neurodegenerative Diseasesmentioning

confidence: 97%

“…We have, using proteomic analysis of deiminated proteins in the injured CNS [32,33,36], identified several proteins with neurodegenerative implications including neuroinflammation, perivascular drainage of Aβ, and the SNARE proteins, which are involved in EV release [139,140]. In pilot studies, using iPSC neuronal models derived from fibroblasts from patients [37] carrying valosin-protein containing mutations VCPR155C and VCPR191Q we have observed significantly increased pan-protein deimination compared to control (non-mutation carrying) neurones, with significant increases in histone H3 deimination in VCPR155C carrying neurones [36]. We also observed similar changes in pan-protein and histone H3 deimination in iPSC derived neurones from patients carrying α-synuclein triplication [39] compared to control neurones [36].…”

Section: Protein Deimination In Neurodegenerative Diseasesmentioning

confidence: 99%

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Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Section: Protein Deimination In Neurodegenerative Diseasessupporting

confidence: 60%

Section: Introductionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 67%

Section: Protein Deimination In Neurodegenerative Diseasesmentioning

confidence: 97%

Section: Protein Deimination In Neurodegenerative Diseasesmentioning

confidence: 99%

See 3 more Smart Citations

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

Self Cite

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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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Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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Protein Deimination in Protein Misfolding Disorders: Modeled in Human Induced Pluripotent Stem Cells (iPSCs)

Cited by 7 publications

References 54 publications

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

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

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

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