Sculpting excitable membranes: voltage-gated ion channel delivery and distribution

Nature reviews. Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Language: Английский

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Integrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy

Brain, Journal Year: 2023, Volume and Issue: 146(7), P. 3049 - 3062

Published: Feb. 2, 2023

Abstract Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy existing treatments. Recent studies on microRNA in preclinical models have begun yield insights into pain-related mechanisms, identifying nociception-related species differences pinpointing potential drug candidates. With aim bridging translational gap towards clinic, we generated a human integrative miRNA mRNA molecular profile epidermis, tissue hosting small nerve fibres, deeply phenotyped cohort patients with sodium channel-related painful neuropathy not responding currently available therapies. We identified four miRNAs strongly discriminating from healthy individuals, confirming their effect differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation post-transcriptional modifications, strong effects including NEDD4. complex epidermal miRNA–mRNA network based tissue-specific experimental data suggesting cross-talk between cells axons pain. Using immunofluorescence assay confocal microscopy, observed that Nav1.7 signal intensity keratinocytes inversely correlated NEDD4 expression was downregulated by miR-30 family, fine tuning protein expression. Our targeted profiling advances understanding specific signatures may accelerate process personalized medicine

Language: Английский

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Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(777)

Published: Dec. 11, 2024

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment determine the extent which keratinocyte activity contributes severe neuropathic accompanies chemotherapy. We found inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical across acute persistent time points from 2 days through 3 weeks. Furthermore, exposure sensitized human stimulation enhanced currents PIEZO1, mechanosensitive channel highly expressed in keratinocytes. Deletion PIEZO1 mice. These findings suggest nonneuronal cutaneous cells substantially pave way development new relief strategies target PIEZO1.

Language: Английский

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Proteomic analysis of isolated nerve terminals from Na_V1.9 knockout mice reveals pathways relevant for neuropathic pain signalling

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 28, 2024

Abstract Neuropathic pain substantially affects the mental and physical well-being of patients magnifies socio-economic burden on healthcare system. It is important to understand molecular mechanisms underlying chronic effectively target it. To investigate peripheral relevant signaling, we isolated nerve terminals from mouse footpads. The contain both pre- post-synaptic proteins are deficient in keratin histone mice humans. We detected protein translational machinery mitochondria observed that they were capable endocytosis. An unbiased proteomic analysis footpads Na V 1.9 knockout shows dysregulation p38 mitogen-activated kinase (MAPK) extracellular regulated 1/2 (ERK1/2) pathways, components involved translation energy metabolism. Isolation human skin punch biopsies, validated by analysis, highlights broad value our approach. Our study thus reveals signaling implicated perception.

Language: Английский

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Neuropathy and pain in Fabry disease

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: July 8, 2024

Fabry disease (FD) is a multiorgan lysosomal storage disorder caused by mutations in the alfa-galactosidase A (GLA ) gene. Pathogenic GLA lead to impaired or even lost enzyme activity, which causes accumulation of sphingolipids, e.g., globotriaosylceramide, cells and tissues. The majority FD patients experience triggerable pain, mainly acral burning, often begins early childhood. While small fiber pathology assumed be basis underlying molecular mechanisms are not well understood. This review summarizes clinical characteristics neuropathy neuropathic pain FD, presents current treatment options, gives an overview latest findings from experimental human model systems on pathomechanisms contributing FD-associated pain.

Language: Английский

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In vitro models

International review of neurobiology, Journal Year: 2024, Volume and Issue: unknown, P. 233 - 278

Published: Jan. 1, 2024

Language: Английский

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Molecular mechanisms of neuropathic pain

International review of neurobiology, Journal Year: 2024, Volume and Issue: unknown, P. 279 - 309

Published: Jan. 1, 2024

Language: Английский

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Altered blood and keratinocyte microRNA/transfer RNA fragment profiles related to fibromyalgia syndrome and its severity

Pain, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 6, 2024

Abstract Fibromyalgia syndrome (FMS) is a debilitating widespread chronic pain condition of unclear pathophysiology. We studied small noncoding RNAs as potential classifiers and mediators FMS. Blood keratinocyte microRNAs (miRs) transfer RNA fragments (tRFs) were profiled by RNA-sequencing within comprehensively phenotyped female cohort 53 patients with FMS vs 34 healthy controls (hCOs) 15 major depression physical (disease controls). Small quantified via candidates validated qRT-PCR. MicroRNAs tRFs tested for association symptoms their regulatory roles. miR tRF profiles altered in compared to hCO whole blood (n = 69; n 22) keratinocytes 41; 55). Receiver operating characteristic analysis hsa-miR-148a-3p hsa-miR-182-5p, candidate tRF-21-WB8647O5D levels separated from hCO. In blood, hsa-miR-182-5p hsa-miR-576-5p upregulation was qRT-PCR, showing even higher expression disease control, while TRF-20-40KK5Y93 selectively increased associated how manifested patients. Keratinocyte correlated loss skin innervation. linked immune processes, whereas keratinocytes, adhesion epithelial functions targeted. Modulated shared sequence motifs FMS, which may promote concerted pathway regulation. Our findings show miRs/tRFs key dysregulation pathophysiology open new perspectives diagnostics, symptom monitoring, clinical management.

Language: Английский

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Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy

Neurobiology of Pain, Journal Year: 2024, Volume and Issue: 17, P. 100176 - 100176

Published: Dec. 17, 2024

Language: Английский

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