Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

Cartelli, Daniele; Cavaletti, Guido; Lauria, Giuseppe; Meregalli, C

doi:10.3390/cells11081358

Cited by 6 publications

(4 citation statements)

References 111 publications

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“…CD36 induced accumulation of lipids in peripheral nerves may indeed overwhelm the capacity of SCs and axons to metabolize these compounds through mitochondrial β-oxidation, the TCA cycle and oxidative phosphorylation to generate ATP. We also found that proteins involved in proteasomal catabolic processes and microtubule biology were downregulated, both parameters being indicative of neurodegenerative processes (40, 41). Furthermore, we found structurally abnormal and dysfunctional mitochondria within unmyelinated Remak bundle fibers of PCSK9 deficient mice.…”

Section: Discussionmentioning

confidence: 70%

PCSK9 deficiency promotes the development of peripheral neuropathy

Jaafar,

Paulo-Ramos,

Rastoldo

et al. 2024

Preprint

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PCSK9 is a serine protease primarily produced and secreted by the liver. Its best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein (LDL) receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL-C metabolism, recent studies have reported pleiotropic biological roles for PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the function and the structural integrity of peripheral nerves are critically influenced by circulating lipids and cholesterol levels, the impact of PCSK9 in the peripheral nervous system is still unexplored. In this study, we investigated the consequences of PCSK9 deficiency on the physiology of peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of mechanical pain sensations. PCSK9 deficient mice also presented skin structural changes with a reduction of number of terminal nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, peripheral nerves of PCSK9 deficient mice presented an upregulation of the fatty acid transporter CD36 expression which correlated with an increase in nerve lipid contents and structural mitochondrial abnormalities. Our findings demonstrate that PCSK9 plays a critical role in the peripheral nerves by regulating lipid homeostasis, and through its impact on CD36, PCSK9 deficiency could lead to the development of symptoms related to peripheral neuropathy.

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Section: Discussionmentioning

confidence: 70%

PCSK9 deficiency promotes the development of peripheral neuropathy

Jaafar,

Paulo-Ramos,

Rastoldo

et al. 2024

Preprint

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“… 81 , 84 , 85 Our integrative miRNA–mRNA profiling identified NEDD4 as a potentially important player in the epidermal microenvironment. NEDD4 is known to participate in the regulation of axonal growth, neuronal hyperexcitability 63 , 86 and Nav1.7 modulation. 63 , 87-89 To investigate its effect on Nav1.7, which has been previously proposed as a potential biomarker for painful neuropathy, 90 we performed IFA in skin biopsy sections from 11 NavNP patients carrying W1538R, L1267V, D1908G and/or V991L/M932L haplotypes and in 18 HC ( Supplementary Table 7 ).…”

Section: Resultsmentioning

confidence: 99%

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

Anđelić

Marcuzzo

Marchi

et al. 2023

Brain

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

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“…Studies have reported that potassium channels play a role in the hyperexcitability of peripheral neuropathy [27,28], and bortezomib has been shown to affect microtubule polymerization and axonal transport in rat DRG neurons [29]. U The ubiquitin proteasome system and microtubules are recognized as master regulators of central and peripheral nervous system axon degeneration [30]. Furthermore, mitochondrial damage and oxidative stress are well-documented events in CIPN [8,31].…”

Section: Gene Interaction Analysis Unveiled Gene Modules Associated W...mentioning

confidence: 99%

Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy

Sun,

Li,

Zhang

et al. 2024

Preprint

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Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.

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Ubiquitin Proteasome System and Microtubules Are Master Regulators of Central and Peripheral Nervous System Axon Degeneration

Cited by 6 publications

References 111 publications

PCSK9 deficiency promotes the development of peripheral neuropathy

PCSK9 deficiency promotes the development of peripheral neuropathy

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

Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy

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