SEARCHOTHERneurology, preclinical research

other·neurology, preclinical research, biomedical research, immunology·PMC10039839

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Molecular Neurobiology · 2 authors, 1 centre

AI SUMMARY

FIDELITY 100%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This preclinical study in mouse models of multiple sclerosis found that intranasal administration of an antisense oligonucleotide targeting the RNA-binding protein HuR attenuated pain hypersensitivity and improved myelin restoration. The mechanism involved either promoting neuroprotection via HuD in a chronic model or suppressing microglial neuroinflammation in a relapsing-remitting model.

Full summary

953 CHARS

The study investigated the role of posttranscriptional regulation by RNA-binding proteins HuR and HuD in demyelination-associated neuropathic pain using mouse models of multiple sclerosis (MOG-EAE for chronic, PLP-EAE for relapsing-remitting). Intranasal treatment with an anti-HuR antisense oligonucleotide (ASO) attenuated mechanical allodynia and motor disability. In MOG-EAE mice, ASO treatment improved demyelination and restored expression of HuD and neuroprotective markers (neurofilament H, GAP43), suggesting a neuron-mediated neuroprotective mechanism. In PLP-EAE mice, ASO treatment reduced microglial activation and neuroinflammation. The study also showed increased spinal myelin content in a peripheral neuropathy model (SNI) after ASO treatment. The findings suggest HuR is a multitarget protein for controlling neuroinflammation and neurodegeneration, and intranasal ASO delivery represents a potential non-invasive therapeutic strategy.

STUDY TYPE

other

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10039839

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Molecular Neurobiology

READ THE FULL PAPER

ABSTRACT

Neuropathic pain is the most difficult-to-treat pain syndrome in multiple sclerosis. Evidence relates neuropathic pain to demyelination, which often originates from unresolved neuroinflammation or altered immune response. Posttranscriptional regulation of gene expression might play a fundamental role in the regulation of these processes. The ELAV RNA-binding proteins HuR and HuD are involved in the promotion of inflammatory phenomena and in neuronal development and maintenance, respectively. Thus, the aim of this study was to investigate the role of HuR and HuD in demyelination-associated neuropathic pain in the mouse experimental autoimmune encephalomyelitis (EAE) model. HuR resulted overexpressed in the spinal cord of MOG 35-55 –EAE and PLP 139-151 –EAE mice and was detected in CD11b + cells. Conversely, HuD was largely downregulated in the MOG–EAE spinal cord, along with GAP43 and neurofilament H, while in PLP-EAE mice, HuD and neuronal markers remained unaltered. Intranasal antisense oligonucleotide (ASO) delivery to knockdown HuR, increased myelin basic protein expression, and Luxol Fast Blue staining in both EAE models, an indication of increased myelin content. These effects temporally coincided with attenuation of pain hypersensitivity. Anti-HuR ASO increased the expression of HuD in GAP43-expressing cells and promoted a HuD-mediated neuroprotective activity in MOG–EAE mice, while in PLP–EAE mice, HuR silencing dampened pro-inflammatory responses mediated by spinal microglia activation. In conclusion, anti-HuR ASO showed myelin protection at analgesic doses with multitarget mechanisms, and it deserves further consideration as an innovative agent to counteract demyelination in neuropathic pain states. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12035-023-03236-8.

CITATION EXPORT

Vittoria Borgonetti, Nicoletta Galeotti. Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein. Molecular Neurobiology. (2023). https://doi.org/10.1007/s12035-023-03236-8

AUTHORS

2 · 1 CENTRES

Vittoria Borgonetti, Nicoletta Galeotti

grid.8404.80000 0004 1757 2304Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, I–50139 Florence, Italy