Immunity, Journal Year: 2024, Volume and Issue: unknown
Published: Dec. 1, 2024
Language: Английский
Frontiers in Neurology, Journal Year: 2022, Volume and Issue: 13
Published: March 11, 2022
The main aim of this review is to summarize the current state-of-art in field childhood Neuronal Ceroid Lipofuscinosis (NCL), a group rare neurodegenerative disorders. These are genetic diseases associated with formation toxic endo-lysosomal storage. Following brief historical evolution NCL definition, clinically-oriented approach used describing how early symptoms and signs affecting motor, visual, cognitive domains, including seizures, may lead clinicians rapid molecular diagnosis, avoiding long diagnostic odyssey commonly observed. We go on focus recent advances research contributions knowledge pathogenic mechanisms underlying NCL. describe large variety experimental models which have aided research, as well most technological developments shed light involved cellular pathology, such apoptosis autophagy. search for innovative therapies described. Translation data into therapeutic approaches being established several NCLs, one drug now commercially available. Lastly, we show importance palliative care symptomatic treatments still interventions.
Language: Английский
Citations
49
Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(5), P. 1775 - 1784
Published: Oct. 14, 2022
Abstract Introduction Synaptic degeneration is a key part of the pathophysiology neurodegenerative diseases, and biomarkers reflecting pathological alterations are greatly needed. Method Seventeen synaptic proteins were quantified in pathology‐confirmed cerebrospinal fluid cohort patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar (FTLD; 53), Lewy body spectrum disorders (LBD; 21), as well healthy controls (HC; 48). Results Comparisons revealed four distinct patterns: markers decreased across all conditions compared to HC (the neuronal pentraxins), increased (14‐3‐3 zeta/delta), selectively AD other (neurogranin beta‐synuclein), LBD FTLD (AP2B1 syntaxin‐1B). Discussion Several may serve for dysfunction AD, LBD, FTLD. Additionally, differential patterns protein seem be present diseases. Highlights A panel using mass spectrometry. We disease, degeneration, disorders. Pathology was confirmed by autopsy or familial mutations. discovered cognitive decline. found
Language: Английский
Citations
40
Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2793 - 2793
Published: Oct. 14, 2023
Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), well a seemingly distinct Niemann-Pick type C with primarily juvenile onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets, microglia, peripheral macrophages, regulatory T cells (Tregs); the complement system; other soluble factors. In this review, we compare these diseases from clinical point of view highlight common pathways mechanisms protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies overlapping dysfunctions diseases. These approaches but not limited immunisation, cascade blockade, microbiome regulation, inhibition signal transduction, Treg boosting, stem transplantation.
Language: Английский
Citations
26
Autophagy, Journal Year: 2023, Volume and Issue: 20(3), P. 590 - 613
Published: Nov. 1, 2023
Although microglial activation is induced by an increase in chemokines, the role of mitophagy this process remains unclear. This study aimed to elucidate CKLF/CKLF1 (chemokine-like factor 1)-induced and neuroinflammation, as well underlying molecular mechanisms following CKLF treatment. determined that CKLF, inducible chemokine brain, leads markers, such DNM1L, PINK1 (PTEN putative kinase 1), PRKN, OPTN, along with a simultaneous autophagosome formation, evidenced elevated levels BECN1 MAP1LC3B (microtubule-associated protein 1 light chain 3 beta)-II. However, SQSTM1, substrate autophagy, was also accumulated treatment, suggesting flux reduced mitophagosomes accumulated. These findings were confirmed transmission electron microscopy confocal microscopy. The defective observed our caused impaired lysosomal function, including mitophagosome-lysosome fusion, lysosome generation, acidification, resulting accumulation damaged mitochondria cells. Further analysis revealed pharmacological blocking or gene-silencing inhibited CKLF-mediated activation, expression marker AIF1 (allograft inflammatory 1) mRNA proinflammatory cytokines (Tnf Il6). Ultimately, results brains adult mice. In summary, induces mitophagy, inflammation, providing potential approach for treating neuroinflammatory diseases.
Language: Английский
Citations
26
PLoS Biology, Journal Year: 2024, Volume and Issue: 22(4), P. e3002607 - e3002607
Published: April 30, 2024
Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal profiles, one them showing signs poor cognitive function, a faster pace disease progression, shorter survival disease, severe neurodegeneration astrogliosis, reduced levels metabolomic profiles. found this profile be present in affected cortical regions associated higher Braak tau scores significant dysregulation synapse-related genes, endocytosis, phagosome, mTOR signaling pathways altered early late stages. cross-omics integration transcriptomic an SNCA mouse model revealed overlapping signature. Furthermore, leveraged single-nuclei RNA-seq identify distinct cell-types that most likely mediate Lastly, identified clusters uncovered cerebrospinal fluid biomarkers poised monitor progression possibly cognition. Our analyses provide novel critical insights into AD.
Language: Английский
Citations
13
Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2024, Volume and Issue: 379(1899)
Published: Feb. 19, 2024
Over the past two decades, increased research has highlighted connection between endosomal trafficking defects and neurodegeneration. The endo-lysosomal network is an important, complex cellular system specialized in transport of proteins, lipids, other metabolites, essential for cell homeostasis. Disruption this pathway linked to a wide range neurodegenerative diseases, including Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis, Huntington's disease frontotemporal dementia. Furthermore, there strong evidence that create opportunities diagnostic therapeutic intervention. In
Language: Английский
Citations
10
Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 21
Published: Jan. 2, 2025
Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of material. Maintenance lysosomal integrity is essential homeostasis membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes repaired or degraded via lysophagy, during which glycans, exposed on ruptured membranes, recognized by galectins leading to K48- K63-linked poly-ubiquitination (poly-Ub) proteins followed recruitment macroautophagic/autophagic machinery degradation. Linear (M1) poly-Ub, catalyzed linear ubiquitin chain assembly complex (LUBAC) E3 ligase removed OTULIN (OTU deubiquitinase with linkage specificity) exerts important functions in immune signaling survival, but role M1 poly-Ub remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged accumulate an OTULIN- K63 Ub-dependent manner. LMP-induced at damaged contributes lysosome degradation, recruits NFKB (nuclear factor kappa B) modulator IKBKG/NEMO locally activates inhibitor kinase (IKK) trigger activation. Inhibition enhances LMP- OTULIN-regulated death, indicating pro-survival LMP potentially lysophagy. Finally, also occurs primary mouse neurons induced pluripotent stem cell-derived human dopaminergic neurons. Our results reveal novel homeostasis, lysosomes, implications signaling, inflammation death.Abbreviation: ATG: autophagy related; BafA1: bafilomycin A1; CALCOCO2/NDP52: calcium binding coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component nuclear B complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA protein 1-WD repeat FYVE containing 1; DGCs: degradative compartments; DIV: days vitro; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting required transport; FBXO27: F-box 27; GBM: glioblastoma multiforme; IKBKB/IKKB: subunit beta; IKBKG/NEMO: regulatory gamma; IKK: kinase; iPSC: cell; KBTBD7: kelch BTB 7; KO: knockout; LAMP1: associated LCD: death; LGALS: galectin; LMP: permeabilization; LLOMe: ester; LOP: loperamide; LUBAC: LRSAM1: leucine rich sterile alpha motif MAP1LC3/LC3: microtubule 1 light 3; MTOR: mechanistic target rapamycin MTORC1: MTOR NBR1: NBR1 cargo receptor; NFKB/NF-κB: B; NFKBIA/IĸBα: polypeptide gene enhancer B-cells alpha; OPTN: optineurin; ORAS: OTULIN-related autoinflammatory syndrome; OTULIN: OTU specificity; RING: really interesting new gene; RBR: RING-in-between-RING; PLAA: phospholipase A2 activating protein; RBCK1/HOIL-1: RANBP2-type C3HC4-type zinc finger RNF31/HOIP: ring 31; SHARPIN: SHANK RH interactor; SQSTM1/p62: sequestosome SR-SIM: super-resolution-structured illumination microscopy; TAX1BP1: Tax1 TBK1: TANK TH: tyrosine hydroxylase; TNF/TNFα: tumor necrosis factor; TNFRSF1A/TNFR1-SC: TNF receptor superfamily member 1A TRIM16: tripartite 16; Ub: ubiquitin; UBE2QL1: conjugating enzyme E2 QL1; UBXN6/UBXD1: UBX 6; VCP/p97: valosin WIPI2: WD domain, phosphoinositide interacting YOD1: YOD1 deubiquitinase.
Language: Английский
Citations
1
Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)
Published: Feb. 26, 2025
The TMEM106B gene, encoding a lysosomal membrane protein, is closely linked with brain aging and neurodegeneration. has been identified as risk factor for several neurodegenerative diseases characterized by aggregation of the RNA-binding protein TDP-43, including frontotemporal lobar degeneration (FTLD) limbic-predominant age-related TDP-43 encephalopathy (LATE). To investigate role in proteinopathy, we ablated TDP-43Q331K knock-in mouse line, which expresses an ALS-linked mutation at endogenous levels. We found that deficiency leads to glial activation, Purkinje cell loss, behavioral deficits mice without inducing typical pathology. Interestingly, ablation results significant body weight gain, increased fat deposition, hepatic triglyceride (TG) accumulation mice. In addition, lipidomic transcriptome analysis shows profound alteration lipid metabolism liver TDP-43Q331KTmem106b−/− Our studies reveal novel function provide new insights into their roles An unexpected obesity phenotype altered TMEM106B-deficient metabolism, providing
Language: Английский
Citations
1
Coordination Chemistry Reviews, Journal Year: 2025, Volume and Issue: 534, P. 216552 - 216552
Published: March 3, 2025
Language: Английский
Citations
1
Journal of Applied Toxicology, Journal Year: 2022, Volume and Issue: 43(1), P. 4 - 21
Published: March 14, 2022
Silver nanoparticles have many medical and commercial applications, but their effects on human health are poorly understood. They used extensively in products of daily use, little is known about potential neurotoxic effects. A xenobiotic metal, silver, has no physiological significance the body as a trace metal. Biokinetics silver indicates its elimination from via urine feces route. However, substantial amount evidence both vitro vivo experimental research unequivocally establish fact easier penetration smaller across blood-brain barrier to enter brain thereby interaction with cellular components induce Toxicological rely degree exposure, particle size, surface coating, agglomeration state well type cell or organism evaluate toxicity. This review covers pertinent facts present knowledge neurotoxicity reviewing impacts oxidative stress, neuroinflammation, mitochondrial function, neurodegeneration, apoptosis, necrosis. The effect central nervous system topic growing interest concern that requires immediate consideration.
Language: Английский
Citations
36