Methods in molecular biology, Год журнала: 2024, Номер unknown
Опубликована: Янв. 1, 2024
Язык: Английский
Annual Review of Biochemistry, Год журнала: 2024, Номер 93(1), С. 261 - 287
Опубликована: Апрель 15, 2024
Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein that phosphorylates specific subset ∼65 human Rab GTPases, which are master regulators secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose capacity to bind cognate effector proteins guanine nucleotide exchange factors. Moreover, phosphorylated cannot interact with their prenyl-binding retrieval (also known as dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, gain phospho-Rab-specific proteins, such RILPL1, resulting pathological consequences. also act upstream controlling its activation recruitment onto membranes. signaling counteracted phosphoprotein phosphatase PPM1H, selectively dephosphorylates phospho-Rab proteins. We present here our current understanding structure, biochemical properties, cell biology related paralog LRRK1 discuss how this information guides generation inhibitors for potential benefit patients.
Язык: Английский
Процитировано
28
Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15
Опубликована: Ноя. 2, 2023
Alzheimer's disease (AD) is characterized by the accumulation of misfolded amyloid-beta and tau proteins. Autophagy acts as a proteostasis process to remove protein clumps, although it progressively weakens with aging AD, thus facilitating toxic proteins causing neurodegeneration. This review examines impact impaired autophagy on progression AD pathology. Under normal circumstances, removes abnormal damaged organelles, but any dysfunction in this can lead exacerbation amyloid pathology, particularly AD. There increasing attention therapeutic tactics revitalize autophagy, including reduced caloric intake, autophagy-stimulating drugs, genetic therapy. However, translation these strategies into clinical practice faces several hurdles. In summary, integrates understanding intricate role reinforces promising prospects beneficial target for treatments modify course disease.
Язык: Английский
Процитировано
27
Neuron, Год журнала: 2023, Номер 111(15), С. 2329 - 2347.e7
Опубликована: Июнь 5, 2023
Autophagy disorders prominently affect the brain, entailing neurodevelopmental and neurodegenerative phenotypes in adolescence or aging, respectively. Synaptic behavioral deficits are largely recapitulated mouse models with ablation of autophagy genes brain cells. Yet, nature temporal dynamics autophagic substrates remain insufficiently characterized. Here, we immunopurified LC3-positive vesicles (LC3-pAVs) from proteomically profiled their content. Moreover, characterized LC3-pAV content that accumulates after macroautophagy impairment, validating a degradome. We reveal selective pathways for aggrephagy, mitophagy, ER-phagy via receptors, turnover numerous synaptic substrates, under basal conditions. To gain insight into protein turnover, quantitatively compared adolescent, adult, aged brains, revealing critical periods enhanced mitophagy degradation substrates. Overall, this resource unbiasedly characterizes contribution to proteostasis maturing, brain.
Язык: Английский
Процитировано
25
Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(7), С. 2815 - 2853
Опубликована: Апрель 24, 2024
Regulated cell death (RCD) is a controlled form of orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, modulating immunity. Accumulating evidence has recently revealed that evasion frequently the primary cause tumor survival. Several have garnered attention promising cancer therapies due their ability induce regression prevent relapse, comparable apoptosis. Moreover, they offer potential solutions for overcoming acquired resistance tumors toward drugs. With an increasing understanding underlying mechanisms governing these subroutines, growing number small-molecule compounds targeting single multiple pathways been discovered, providing novel strategies current therapy. In this review, we comprehensively summarized regulatory emerging mainly including autophagy-dependent death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic NETotic lysosome-dependent immunogenic (ICD). Furthermore, focused on discussing related compounds. brief, insightful findings may provide valuable guidance investigating individual collaborative approaches towards different ultimately driving discovery target significantly enhance future therapeutics.
Язык: Английский
Процитировано
12
Cold Spring Harbor Perspectives in Biology, Год журнала: 2023, Номер 15(8), С. a041415 - a041415
Опубликована: Июнь 5, 2023
Extracellular vesicles, such as exosomes, can be used interesting models to study the structure and function of biological membranes these vesicles contain only one membrane (i.e., lipid bilayer). In addition lipids, they proteins, nucleic acids, various other molecules. The composition exosomes is here compared HIV particles detergent-resistant membranes, which also have a high content sphingolipids, cholesterol, phosphatidylserine (PS). We discuss interactions between lipids in two bilayers, especially those PS 18:0/18:1 inner leaflet very-long-chain sphingolipids outer leaflet, importance cholesterol for interactions. briefly involvement ether-linked phospholipids (PLs) raft-like structures, possible classes formation exosomes. urgent need improve quality quantitative lipidomic studies highlighted.
Язык: Английский
Процитировано
20
Alzheimer s & Dementia, Год журнала: 2023, Номер 19(12), С. 5355 - 5370
Опубликована: Май 16, 2023
Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance Tau in healthy neurons, is finding demented Alzheimer's disease (AD) patients. However, association autophagy with maintenance cognitive integrity resilient individuals who have AD neuropathology but remain non-demented (NDAN) has not been evaluated.
Язык: Английский
Процитировано
19
Autophagy, Год журнала: 2024, Номер 20(7), С. 1577 - 1596
Опубликована: Март 18, 2024
Streptococcus pneumoniae (S. pneumoniae) represents a major human bacterial pathogen leading to high morbidity and mortality in children the elderly. Recent research emphasizes role of extracellular vesicles (EVs) pathogenicity. However, contribution S. EVs (pEVs) host-microbe interactions has remained unclear. Here, we observed that infections mice led severe lung injuries alveolar epithelial barrier (AEB) dysfunction. Infections reduced protein expression tight junction OCLN (occludin) activated macroautophagy/autophagy tissues A549 cells. Mechanically, induced autophagosomal degradation AEB impairment monolayer. released pEVs could be internalized by Through proteomics, profiled cargo proteins inside found these contained many virulence factors, among which identified eukaryotic-like serine-threonine kinase StkP. The StkP induce phosphorylation BECN1 (beclin 1) at Ser93 Ser96 sites, initiating autophagy resulting autophagy-dependent Finally, deletion stkP completely protected infected from death, significantly alleviated vivo, largely abolished disruption caused vitro. Overall, our results suggested played crucial spread factors. communicate with host target even hijack initiation pathway, contributing
Язык: Английский
Процитировано
9
Transplant Immunology, Год журнала: 2024, Номер 83, С. 102006 - 102006
Опубликована: Фев. 9, 2024
Язык: Английский
Процитировано
7
Advanced Science, Год журнала: 2024, Номер 11(31)
Опубликована: Июнь 18, 2024
Abstract Non‐alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator in lysosomal degradation, reported to exacerbate steatosis NAFLD mice and patients, indicating its probability being therapeutic target for treatment. In this study, the potential Rubicon blockage investigated. Lipid nanoparticles carrying Rubicon‐specific CRISPR‐Cas9 components exhibited accumulation, cell internalization, knockdown. A single administration results attenuated lipid deposition steatosis, lower circulating levels decreased adipocyte size mice. Furthermore, increase phosphatidylcholine phosphatidylethanolamine can be observed livers after silencing, along regulatory effects on metabolism‐related genes such as CD36, Gpcpd1, Chka, Lpin2. The indicate that knockdown improves glycerophospholipid metabolism thereby ameliorates progression, which provides strategy therapy via restoration Rubicon.
Язык: Английский
Процитировано
7
Nature Communications, Год журнала: 2025, Номер 16(1)
Опубликована: Фев. 4, 2025
The leukocyte integrin LFA1 is indispensable for immune responses, orchestrating lymphocyte trafficking and adhesion. While activation induces clustering at the cell contact surface via outside-in signaling, regulatory mechanisms remain unclear. Here, we uncovered a previously hidden function of autophagosome component LC3 beyond its role in autophagy by bridging two seemingly unrelated pathways: transport transport. clusters co-trafficked with LC3, facilitating accumulation surface. LC3b knockout decreased adhesiveness. did not induce autophagy, whereas it increased mTOR AMPK activity. LFA1-dependent enhances Inhibiting Mst1 kinase-mediated phosphorylation promoted LC3-mediated recruitment to through direct interaction RAPL, uncovering an unprecedented route. These findings uncover expand our understanding regulation LFA1. required canonical non-canonical autophagy. authors LAPTIN, triggered which activates drive co-clustering thereby increasing
Язык: Английский
Процитировано
1