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Article ; Online: Dysregulation of Human Juvenile Huntington's Disease Brain Proteomes in Cortex and Putamen Involves Mitochondrial and Neuropeptide Systems.

Podvin, Sonia / Mosier, Charles / Poon, William / Wei, Enlin / Rossitto, Leigh-Ana / Hook, Vivian

2023 Volume 12, Issue 4, Page(s) 315–333

Abstract: Background: Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat CAG expansions in the human HTT gene. Early onset juvenile HD (JHD) in children is the most severe form of the disease caused by high CAG repeat ... ...

Abstract	Background: Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat CAG expansions in the human HTT gene. Early onset juvenile HD (JHD) in children is the most severe form of the disease caused by high CAG repeat numbers of the HTT gene. Objective: To gain understanding of human HD mechanisms hypothesized to involve dysregulated proteomes of brain regions that regulate motor and cognitive functions, this study analyzed the proteomes of human JHD cortex and putamen brain regions compared to age-matched controls. Methods: JHD and age-matched control brain tissues were assessed for CAG repeat numbers of HTT by PCR. Human brain JHD brain cortex regions of BA4 and BA6 with the putamen region (n = 5) were analyzed by global proteomics, compared to age-matched controls (n = 7). Protein interaction pathways were assessed by gene ontology (GO), STRING-db, and KEGG bioinformatics. Results: JHD brain tissues were heterozygous for one mutant HTT allele containing 60 to 120 CAG repeats, and one normal HTT allele with 10 to 19 CAG repeats. Proteomics data for JHD brain regions showed dysregulated mitochondrial energy pathways and changes in synaptic systems including peptide neurotransmitters. JHD compared to control proteomes of cortex and putamen displayed (a) proteins present only in JHD, (b) proteins absent in JHD, and (c) proteins that were downregulated or upregulated. Conclusions: Human JHD brain cortex and putamen regions display significant dysregulation of proteomes representing deficits in mitochondrial and synaptic neurotransmission functions. These findings advance understanding of JHD brain molecular mechanisms associated with HD disabilities.
MeSH term(s)	Child ; Humans ; Putamen ; Proteome ; Huntington Disease/genetics ; Neurodegenerative Diseases ; Brain ; Neuropeptides
Chemical Substances	Proteome ; Neuropeptides
Language	English
Publishing date	2023-12-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2673033-9
ISSN	1879-6400 ; 1879-6397
ISSN (online)	1879-6400
ISSN	1879-6397
DOI	10.3233/JHD-230577
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Article ; Online: Distinct Cleavage Properties of Cathepsin B Compared to Cysteine Cathepsins Enable the Design and Validation of a Specific Substrate for Cathepsin B over a Broad pH Range.

Yoon, Michael C / Phan, Von / Podvin, Sonia / Mosier, Charles / O'Donoghue, Anthony J / Hook, Vivian

Biochemistry

2023 Volume 62, Issue 15, Page(s) 2289–2300

Abstract: The biological and pathological functions of cathepsin B occur in acidic lysosomes and at the neutral pH of cytosol, nuclei, and extracellular locations. Importantly, cathepsin B displays different substrate cleavage properties at acidic pH compared to ... ...

Abstract	The biological and pathological functions of cathepsin B occur in acidic lysosomes and at the neutral pH of cytosol, nuclei, and extracellular locations. Importantly, cathepsin B displays different substrate cleavage properties at acidic pH compared to neutral pH conditions. It is, therefore, desirable to develop specific substrates for cathepsin B that measure its activity over broad pH ranges. Current substrates used to monitor cathepsin B activity consist of Z-Phe-Arg-AMC and Z-Arg-Arg-AMC, but they lack specificity since they are cleaved by other cysteine cathepsins. Furthermore, Z-Arg-Arg-AMC monitors cathepsin B activity at neutral pH and displays minimal activity at acidic pH. Therefore, the purpose of this study was to design and validate specific fluorogenic peptide substrates that can monitor cathepsin B activity over a broad pH range from acidic to neutral pH conditions. In-depth cleavage properties of cathepsin B were compared to those of the cysteine cathepsins K, L, S, V, and X via multiplex substrate profiling by mass spectrometry at pH 4.6 and pH 7.2. Analysis of the cleavage preferences predicted the tripeptide Z-Nle-Lys-Arg-AMC as a preferred substrate for cathepsin B. Significantly, Z-Nle-Lys-Arg-AMC displayed the advantageous properties of measuring high cathepsin B specific activity over acidic to neutral pHs and was specifically cleaved by cathepsin B over the other cysteine cathepsins. Z-Nle-Lys-Arg-AMC specifically monitored cathepsin B activity in neuronal and glial cells which were consistent with relative abundances of cathepsin B protein. These findings validate Z-Nle-Lys-Arg-AMC as a novel substrate that specifically monitors cathepsin B activity over a broad pH range.
MeSH term(s)	Cathepsin B/metabolism ; Cathepsins/metabolism ; Cysteine ; Endopeptidases/metabolism ; Lysosomes/metabolism ; Peptides ; Substrate Specificity
Chemical Substances	Cathepsin B (EC 3.4.22.1) ; Cathepsins (EC 3.4.-) ; Cysteine (K848JZ4886) ; Endopeptidases (EC 3.4.-) ; Peptides
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.3c00139
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Article ; Online: Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.

Podvin, Sonia / Rosenthal, Sara Brin / Poon, William / Wei, Enlin / Fisch, Kathleen M / Hook, Vivian

Journal of Huntington's disease

2022 Volume 11, Issue 3, Page(s) 243–267

Abstract: Background: Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat (CAG) expansions in the human HTT gene encoding the huntingtin protein (Htt) with an expanded polyglutamine tract.: Objective: HD models from ... ...

Abstract	Background: Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat (CAG) expansions in the human HTT gene encoding the huntingtin protein (Htt) with an expanded polyglutamine tract. Objective: HD models from yeast to transgenic mice have investigated proteins interacting with mutant Htt that may initiate molecular pathways of cell death. There is a paucity of datasets of published Htt protein interactions that include the criteria of 1) defining fragments or full-length Htt forms, 2) indicating the number of poly-glutamines of the mutant and wild-type Htt forms, and 3) evaluating native Htt interaction complexes. This research evaluated such interactor data to gain understanding of Htt dysregulation of cellular pathways. Methods: Htt interacting proteins were compiled from the literature that meet our criteria and were subjected to network analysis via clustering, gene ontology, and KEGG pathways using rigorous statistical methods. Results: The compiled data of Htt interactors found that both mutant and wild-type Htt interact with more than 2,971 proteins. Application of a community detection algorithm to all known Htt interactors identified significant signal transduction, membrane trafficking, chromatin, and mitochondrial clusters, among others. Binomial analyses of a subset of reported protein interactor information determined that chromatin organization, signal transduction and endocytosis were diminished, while mitochondria, translation and membrane trafficking had enriched overall edge effects. Conclusion: The data support the hypothesis that mutant Htt disrupts multiple cellular processes causing toxicity. This dataset is an open resource to aid researchers in formulating hypotheses of HD mechanisms of pathogenesis.
MeSH term(s)	Animals ; Humans ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism ; Huntington Disease/metabolism ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurodegenerative Diseases ; Nuclear Proteins/genetics ; Protein Interaction Maps/genetics
Chemical Substances	Huntingtin Protein ; Nerve Tissue Proteins ; Nuclear Proteins
Language	English
Publishing date	2022-07-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2673033-9
ISSN	1879-6400 ; 1879-6397
ISSN (online)	1879-6400
ISSN	1879-6397
DOI	10.3233/JHD-220538
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Article: Emerging evidence for dysregulated proteome cargoes of tau-propagating extracellular vesicles driven by familial mutations of tau and presenilin.

Hook, Vivian / Podvin, Sonia / Mosier, Charles / Boyarko, Ben / Seyffert, Laura / Stringer, Haley / Rissman, Robert A

Extracellular vesicles and circulating nucleic acids

2023 Volume 4, Issue 4, Page(s) 588–598

Abstract: Tau propagation, pathogenesis, and neurotoxicity are hallmarks of neurodegenerative diseases that result in cognitive impairment. Tau accumulates in Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), ... ...

Abstract	Tau propagation, pathogenesis, and neurotoxicity are hallmarks of neurodegenerative diseases that result in cognitive impairment. Tau accumulates in Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy, and related tauopathies. Knowledge of the mechanisms for tau propagation in neurodegeneration is necessary for understanding the development of dementia. Exosomes, known as extracellular vesicles (EVs), have emerged as participants in promoting tau propagation. Recent findings show that EVs generated by neurons expressing familial mutations of tauopathies of FTDP-17 (P301L and V337M) (mTau) and presenilin (A246E) (mPS1) in AD induce tau propagation and accumulation after injection into rodent brain. To gain knowledge of the proteome cargoes of the mTau and mPS1 EVs that promote tau pathogenesis, this review compares the proteomes of these EVs, which results in important new questions concerning EV mechanisms of tau pathogenesis. Proteomics data show that EVs produced by mTau- and mPS1-expressing iPSC neurons share proteins involved in exocytosis and vesicle secretion and, notably, these EVs also possess differences in protein components of vesicle-mediated transport, extracellular functions, and cell adhesion. It will be important for future studies to gain an understanding of the breadth of familial genetic mutations of tau, presenilin, and other genes in promoting EV initiation of tau propagation and pathogenesis. Furthermore, elucidation of EV cargo components that mediate tau propagation will have potential as biomarkers and therapeutic strategies to ameliorate dementia of tauopathies.
Language	English
Publishing date	2023-11-21
Publishing country	United States
Document type	Journal Article
DOI	10.20517/evcna.2023.44
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Article ; Online: Human iN neuronal model of schizophrenia displays dysregulation of chromogranin B and related neuropeptide transmitter signatures.

Podvin, Sonia / Jones, Jeffrey / Kang, Austin / Goodman, Ryan / Reed, Patrick / Lietz, Christopher B / Then, Joshua / Lee, Kelly C / Eyler, Lisa T / Jeste, Dilip V / Gage, Fred H / Hook, Vivian

Molecular psychiatry

2024

Abstract: Schizophrenia (SZ) is a serious mental illness and neuropsychiatric brain disorder with behavioral symptoms that include hallucinations, delusions, disorganized behavior, and cognitive impairment. Regulation of such behaviors requires utilization of ... ...

Abstract	Schizophrenia (SZ) is a serious mental illness and neuropsychiatric brain disorder with behavioral symptoms that include hallucinations, delusions, disorganized behavior, and cognitive impairment. Regulation of such behaviors requires utilization of neurotransmitters released to mediate cell-cell communication which are essential to brain functions in health and disease. We hypothesized that SZ may involve dysregulation of neurotransmitters secreted from neurons. To gain an understanding of human SZ, induced neurons (iNs) were derived from SZ patients and healthy control subjects to investigate peptide neurotransmitters, known as neuropeptides, which represent the major class of transmitters. The iNs were subjected to depolarization by high KCl in the culture medium and the secreted neuropeptides were identified and quantitated by nano-LC-MS/MS tandem mass spectrometry. Several neuropeptides were identified from schizophrenia patient-derived neurons, including chromogranin B (CHGB), neurotensin, and natriuretic peptide. Focusing on the main secreted CHGB neuropeptides, results revealed differences in SZ iNs compared to control iN neurons. Lower numbers of distinct CHGB peptides were found in the SZ secretion media compared to controls. Mapping of the peptides to the CHGB precursor revealed peptides unique to either SZ or control, and peptides common to both conditions. Also, the iNs secreted neuropeptides under both KCl and basal (no KCl) conditions. These findings are consistent with reports that chromogranin B levels are reduced in the cerebrospinal fluid and specific brain regions of SZ patients. These findings suggest that iNs derived from SZ patients can model the decreased CHGB neuropeptides observed in human SZ.
Language	English
Publishing date	2024-02-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-024-02422-x
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Zs.A 4812: Show issues

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Article: Human brain gene expression profiles of the cathepsin V and cathepsin L cysteine proteases, with the PC1/3 and PC2 serine proteases, involved in neuropeptide production

Podvin, Sonia / Wojnicz, Aneta / Hook, Vivian

Heliyon. 2018 July, v. 4, no. 7

2018

Abstract: Proteases are required to generate active peptide neurotransmitters, known as neuropeptides, from pro-neuropeptides. Model animal systems have recently illustrated roles for the cathepsin V (CTSV) and cathepsin L (CTSL) cysteine proteases, combined with ... ...

Abstract	Proteases are required to generate active peptide neurotransmitters, known as neuropeptides, from pro-neuropeptides. Model animal systems have recently illustrated roles for the cathepsin V (CTSV) and cathepsin L (CTSL) cysteine proteases, combined with the serine proteases PC1/3 (PCSK1) and PC2 (PCSK2), and exopeptidases in the production of neuropeptides. There is notable interest in the human-specific cathepsin V gene which is not present in rodent and other animal models used in prior studies of neuropeptide production. A gap in the field is knowledge of the human brain gene expression patterns of these neuropeptide-producing protease systems. Therefore, the goal of this study was to characterize the expression profiles of these pro-neuropeptide processing proteases in human brain. Quantitative gene expression microarray data for 169 human brain regions was obtained from the Allen Institute Human Brain Atlas resource, analyzed as log₂ of gene expression intensity normalized to the mean of human genes (21,245 genes) expressed in human brain. These proteases had log₂ values of 2–12, indicating expression levels above the average of all genes in the human brain, with varying expression levels among the 169 brain regions. CTSV and CTSL displayed moderate to high expression values of 1.9–8.6 and 7.1–10.6, respectively. Interestingly, CTSV and CTSL showed high expression in white matter composed of myelinated axons, consistent with the knowledge that neuropeptide production occurs in axons within transported neuropeptide secretory vesicles to nerve terminals. PCSK1 had a broad range of moderate to very high expression with log₂ of 2–12. PCSK2 had somewhat lower expression levels than PCSK1. The exopeptidase genes RNPEP, CTSH, and CPE each showed fairly even levels of expression throughout the brain, with CPE displaying high expression. The prevalence of these processing proteases throughout human brain regions, including areas rich in neuropeptides such as hypothalamus, is consistent with their roles for neuropeptide production. Further, proenkephalin and NPY precursors, substrates of CTSV and CTSL shown in prior model animal studies, were co-expressed with CTSV and CTSL. These data demonstrate that the human brain expresses the neuropeptide-producing cysteine and serine proteases, with exopeptidases, throughout a multitude of brain regions.
Keywords	cathepsin L ; cathepsin V ; cysteine ; gene expression ; genes ; humans ; hypothalamus ; microarray technology ; neuropeptides ; neurotransmitters ; rodents ; serine proteinases
Language	English
Dates of publication	2018-07
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2018.e00673
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Article: Human brain gene expression profiles of the cathepsin V and cathepsin L cysteine proteases, with the PC1/3 and PC2 serine proteases, involved in neuropeptide production.

Podvin, Sonia / Wojnicz, Aneta / Hook, Vivian

Heliyon

2018 Volume 4, Issue 7, Page(s) e00673

Abstract	Proteases are required to generate active peptide neurotransmitters, known as neuropeptides, from pro-neuropeptides. Model animal systems have recently illustrated roles for the cathepsin V (CTSV) and cathepsin L (CTSL) cysteine proteases, combined with the serine proteases PC1/3 (PCSK1) and PC2 (PCSK2), and exopeptidases in the production of neuropeptides. There is notable interest in the human-specific cathepsin V gene which is not present in rodent and other animal models used in prior studies of neuropeptide production. A gap in the field is knowledge of the human brain gene expression patterns of these neuropeptide-producing protease systems. Therefore, the goal of this study was to characterize the expression profiles of these pro-neuropeptide processing proteases in human brain. Quantitative gene expression microarray data for 169 human brain regions was obtained from the Allen Institute Human Brain Atlas resource, analyzed as log
Language	English
Publishing date	2018-07-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2018.e00673
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Article ; Online: Lysosomal Cathepsin Protease Gene Expression Profiles in the Human Brain During Normal Development.

Hsu, Amy / Podvin, Sonia / Hook, Vivian

Journal of molecular neuroscience : MN

2018 Volume 65, Issue 4, Page(s) 420–431

Abstract: Cathepsin protease genes are necessary for protein homeostasis in normal brain development and function. The diversity of the 15 cathepsin protease activities raises the question of what are the human brain expression profiles of the cathepsin genes ... ...

Abstract	Cathepsin protease genes are necessary for protein homeostasis in normal brain development and function. The diversity of the 15 cathepsin protease activities raises the question of what are the human brain expression profiles of the cathepsin genes during development from prenatal and infancy to childhood, adolescence, and young adult stages. This study, therefore, evaluated the cathepsin gene expression profiles in 16 human brain regions during development by quantitative RNA-sequencing data obtained from the Allen Brain Atlas resource. Total expression of all cathepsin genes was the lowest at the early prenatal stage which became increased at the infancy stage. During infancy to young adult phases, total gene expression was similar. Interestingly, the rank ordering of gene expression among the cathepsins was similar throughout the brain at the age periods examined, showing (a) high expression of cathepsins B, D, and F; (b) moderate expression of cathepsins A, L, and Z; (c) low expression of cathepsins C, H, K, O, S, and V; and (d) very low expression of cathepsins E, G, and W. Results show that the human brain utilizes well-defined, balanced patterns of cathepsin gene expression throughout the different stages of human brain development. Knowledge gained by this study of the gene expression profiles of lysosomal cathepsin proteases among human brain regions during normal development is important for advancing future investigations of how these cathepsins are dysregulated in lysosomal-related brain disorders that affect infants, children, adolescents, and young adults.
MeSH term(s)	Adolescent ; Brain/embryology ; Brain/growth & development ; Brain/metabolism ; Cathepsins/genetics ; Cathepsins/metabolism ; Child ; Child, Preschool ; Female ; Gene Expression Regulation, Developmental ; Humans ; Infant ; Male ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Young Adult
Chemical Substances	RNA, Messenger ; Cathepsins (EC 3.4.-)
Language	English
Publishing date	2018-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	1043392-2
ISSN	1559-1166 ; 0895-8696
ISSN (online)	1559-1166
ISSN	0895-8696
DOI	10.1007/s12031-018-1110-6
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Zs.A 3006: Show issues

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Article ; Online: Distinct Dibasic Cleavage Specificities of Neuropeptide-Producing Cathepsin L and Cathepsin V Cysteine Proteases Compared to PC1/3 and PC2 Serine Proteases.

Yoon, Michael C / Ames, Janneca / Mosier, Charles / Jiang, Zhenze / Podvin, Sonia / O'Donoghue, Anthony J / Hook, Vivian

ACS chemical neuroscience

2022 Volume 13, Issue 2, Page(s) 245–256

Abstract: Neuropeptides, functioning as peptide neurotransmitters and hormones, are generated from proneuropeptide precursors by proteolytic processing at dibasic residue sites (i.e., KR, RK, KK, RR). The cysteine proteases cathepsin L and cathepsin V, combined ... ...

Abstract	Neuropeptides, functioning as peptide neurotransmitters and hormones, are generated from proneuropeptide precursors by proteolytic processing at dibasic residue sites (i.e., KR, RK, KK, RR). The cysteine proteases cathepsin L and cathepsin V, combined with the serine proteases proprotein convertases 1 and 2 (PC1/3 and PC2), participate in proneuropeptide processing to generate active neuropeptides. To compare the dibasic cleavage properties of these proteases, this study conducted global, unbiased substrate profiling of these processing proteases using a diverse peptide library in multiplex substrate profiling by mass spectrometry (MSP-MS) assays. MSP-MS utilizes a library of 228 14-mer peptides designed to contain all possible protease cleavage sites, including the dibasic residue sites of KR, RK, KK, and RR. The comprehensive MSP-MS analyses demonstrated that cathepsin L and cathepsin V cleave at the N-terminal side and between the dibasic residues (e.g., ↓K↓R, ↓R↓K, and K↓K), with a preference for hydrophobic residues at the P2 position of the cleavage site. In contrast, the serine proteases PC1/3 and PC2 displayed cleavage at the C-terminal side of dibasic residues of a few peptide substrates. Further analyses with a series of dipeptide-AMC and tripeptide-AMC substrates containing variant dibasic sites with hydrophobic P2 residues indicated the preferences of cathepsin L and cathepsin V to cleave between dibasic residue sites with preferences for flanking hydrophobic residues at the P2 position consisting of Leu, Trp, Phe, and Tyr. Such hydrophobic amino acids reside in numerous proneuropeptides such as pro-NPY and proenkephalin that are known to be processed by cathepsin L. Notably, cathepsin L displayed the highest specific activity that was 10-, 64-, and 1268-fold greater than cathepsin V, PC1/3, and PC2, respectively. Peptide-AMC substrates with dibasic residues confirmed that PC1/3 and P2 cleaved almost exclusively at the C-terminal side of dibasic residues. These data demonstrate distinct dibasic cleavage site properties and a broad range of proteolytic activities of cathepsin L and cathepsin V, compared to PC1/3 and PC2, which participate in producing neuropeptides for cell-cell communication.
MeSH term(s)	Amino Acid Sequence ; Cathepsin L/metabolism ; Cathepsins ; Cysteine Proteases ; Protein Processing, Post-Translational ; Serine Endopeptidases ; Serine Proteases
Chemical Substances	Cathepsins (EC 3.4.-) ; Cysteine Proteases (EC 3.4.-) ; Serine Proteases (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; Cathepsin L (EC 3.4.22.15)
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.1c00653
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Article ; Online: Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimer's Disease Brain.

Podvin, Sonia / Jiang, Zhenze / Boyarko, Ben / Rossitto, Leigh-Ana / O'Donoghue, Anthony / Rissman, Robert A / Hook, Vivian

ACS chemical neuroscience

2022 Volume 13, Issue 13, Page(s) 1992–2005

Abstract: Synaptic dysfunction and loss occur in Alzheimer's disease (AD) brains, which results in cognitive deficits and brain neurodegeneration. Neuropeptides comprise the major group of synaptic neurotransmitters in the nervous system. This study evaluated ... ...

Abstract	Synaptic dysfunction and loss occur in Alzheimer's disease (AD) brains, which results in cognitive deficits and brain neurodegeneration. Neuropeptides comprise the major group of synaptic neurotransmitters in the nervous system. This study evaluated neuropeptide signatures that are hypothesized to differ in human AD brain compared to age-matched controls, achieved by global neuropeptidomics analysis of human brain cortex synaptosomes. Neuropeptidomics demonstrated distinct profiles of neuropeptides in AD compared to controls consisting of neuropeptides derived from chromogranin A (CHGA) and granins, VGF (nerve growth factor inducible), cholecystokinin, and others. The differential neuropeptide signatures indicated differences in proteolytic processing of their proneuropeptides. Analysis of cleavage sites showed that dibasic residues at the N-termini and C-termini of neuropeptides were the main sites for proneuropeptide processing, and data also showed that the AD group displayed differences in preferred residues adjacent to the cleavage sites. Notably, tau peptide signatures differed in the AD compared to age-matched control human brain cortex synaptosomes. Unique tau peptides were derived from the tau protein through proteolysis using similar and differential cleavage sites in the AD brain cortex compared to the control. Protease profiles differed in the AD compared to control, indicated by proteomics data. Overall, these results demonstrate that dysregulation of neuropeptides and tau peptides occurs in AD brain cortex synaptosomes compared to age-matched controls, involving differential cleavage site properties for proteolytic processing of precursor proteins. These dynamic changes in neuropeptides and tau peptide signatures may be associated with the severe cognitive deficits of AD.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Humans ; Neuropeptides/analysis ; Neuropeptides/metabolism ; Peptides/metabolism ; Proteolysis ; tau Proteins/analysis ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Neuropeptides ; Peptides ; tau Proteins
Language	English
Publishing date	2022-06-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00222
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