Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Язык: Английский

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Microglia and Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(21), С. 12990 - 12990

Опубликована: Окт. 27, 2022

There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) neuroinflammation seems be one of the most fascinating solutions. The primary cell type that performs immunosurveillance helps clear out unwanted chemicals from brain microglia. Microglia work reestablish efficiency stop further degeneration in early stages AD but mainly fail illness’s later phases. This may caused by number reasons, e.g., protracted exposure cytokines induce inflammation an inappropriate accumulation amyloid beta (Aβ) peptide. Extracellular and/or intraneuronal phosphorylated tau can both activate activation TLRs scavenger receptors, inducing numerous inflammatory pathways, including NF-kB, JAK-STAT, NLRP3 inflammasome, facilitates microglial phagocytosis response these mediators. Aβ/tau are taken up microglia, their removal extracellular space also have protective effects, if illness worsens, environment constantly inflamed overexposed oxidative might encourage continuous activation, which lead neuroinflammation, stress, iron overload, neurotoxicity. complexity diversity roles microglia play health necessitate urgent development new biomarkers identify activity different It imperative comprehend intricate mechanisms result impairment develop immunomodulating therapies primarily attempt recover physiological role allowing them carry core function protection.

Язык: Английский

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Electroacupuncture ameliorates beta-amyloid pathology and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB)

Autophagy, Год журнала: 2021, Номер 17(11), С. 3833 - 3847

Опубликована: Фев. 23, 2021

Alzheimer disease (AD) is the most prevalent neurodegenerative disorder leading to dementia in elderly. Unfortunately, no cure for AD available date. Increasing evidence has proved roles of misfolded protein aggregation due impairment macroautophagy/autophagy-lysosomal pathway (ALP) pathogenesis AD, and thus making TFEB (transcription factor EB), which orchestrates ALP, as a promising target treating AD. As complementary therapy, acupuncture or electroacupuncture (EA) been commonly used human diseases. Although beneficial effects have primarily studied both pre-clinically clinically, real efficacy on remains inconclusive underlying mechanisms are largely unexplored. In this study, we demonstrated cognitive-enhancing effect three-needle EA (TNEA) an animal model with beta-amyloid (Aβ) pathology (5xFAD). TNEA reduced APP (amyloid beta (A4) precursor protein), C-terminal fragments (CTFs) Aβ load, inhibited glial cell activation prefrontal cortex hippocampus 5xFAD. Mechanistically, activated via inhibiting AKT-MAPK1-MTORC1 pathway, promoting ALP brains. Therefore, represents therapy novel mechanism involving activation.Abbreviations Aβ: β-amyloid; AD: disease; AIF1/IBA1: allograft inflammatory 1; AKT1: thymoma viral proto-oncogene ALP: autophagy-lysosomal pathway; APP: amyloid protein; BACE1: beta-site cleaving enzyme CQ: chloroquine; CTFs: fragments; CTSD: cathepsin D; EA: electroacupuncture; FC: fear conditioning; GFAP: fibrillary acidic HI: hippocampus; LAMP1: lysosomal-associated membrane MAP1LC3B/LC3B: microtubule-associated 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated kinase MAPT: tau; MTORC1: mechanistic rapamycin complex MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: cortex; PSEN1: presenilin SQSTM1/p62: sequestosome TFEB: transcription EB; TNEA:

Язык: Английский

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TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease

Science, Год журнала: 2023, Номер 381(6656)

Опубликована: Июль 27, 2023

Aggregation of tau into filamentous inclusions underlies Alzheimer's disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis tauopathies remains unclear, which impedes the development disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. promoted proteasomal degradation mutant as well superfluous normal tau. It also enhanced solubility acting both molecular chaperone to prevent misfolding disaggregase dissolve preformed fibrils. maintained connectivity viability neurons. Intracranial delivery through adeno-associated viruses ameliorated pathology, neuroinflammation, cognitive impairments multiple animal models These results suggest down-regulation contributes restoring expression may represent an effective therapeutic strategy.

Язык: Английский

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Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease

Advanced Materials, Год журнала: 2024, Номер 36(19)

Опубликована: Фев. 23, 2024

Abstract The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction reactive oxygen species overproduction. However, the treatment AD remains challenging owning to hindrance caused by blood–brain barrier (BBB) complex pathology AD. Nasal delivery represents an effective means circumventing BBB delivering drugs brain. In this study, black phosphorus (BP) used as drug carrier, well antioxidant, loaded with aggregation inhibitor, methylene blue (MB), obtain BP‐MB. For intranasal (IN) delivery, thermosensitive hydrogel fabricated cross‐linking carboxymethyl chitosan aldehyde Pluronic F127 (F127‐CHO) micelles. BP‐MB nanocomposite incorporated into BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention controlled release. After IN administration, continuously released delivered brain, exerting synergistic therapeutic effects suppressing neuropathology, restoring function, alleviating neuroinflammation, thus inducing cognitive improvements mouse models These findings highlight potential strategy for brain‐targeted management pathologies

Язык: Английский

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