Journal article
Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
Brain (London, England : 1878), Vol.148(6), pp.1978-1993
06/03/2025
DOI: 10.1093/brain/awae407
PMCID: PMC12129742
PMID: 39979221
Abstract
Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
Details
- Title: Subtitle
- Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
- Creators
- Thierry Touvier - IRCCS Ospedale San RaffaeleFrancesca A Veneri - IRCCS Ospedale San RaffaeleAnke Claessens - IRCCS Ospedale San RaffaeleCinzia Ferri - IRCCS Ospedale San RaffaeleRosa Mastrangelo - IRCCS Ospedale San RaffaeleNoémie Sorgiati - IRCCS Ospedale San RaffaeleFrancesca Bianchi - IRCCS Ospedale San RaffaeleSerena Valenzano - IRCCS Ospedale San RaffaeleUbaldo Del Carro - IRCCS Ospedale San RaffaeleCristina Rivellini - IRCCS Ospedale San RaffaelePhu Duong - University of Wisconsin–MadisonMichael E Shy - University of IowaJeffery W Kelly - Scripps Research InstituteJohn Svaren - University of Wisconsin–MadisonR Luke Wiseman - Scripps Research InstituteMaurizio D'Antonio - IRCCS Ospedale San Raffaele
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.148(6), pp.1978-1993
- DOI
- 10.1093/brain/awae407
- PMID
- 39979221
- PMCID
- PMC12129742
- NLM abbreviation
- Brain
- ISSN
- 1460-2156
- eISSN
- 1460-2156
- Publisher
- OXFORD UNIV PRESS
- Grant note
- Fondazione Telethon: GGP14147, GGP19099 Charcot- Marie-Tooth Association (CMTA)Fondazione Veronesi (postdoctoral fellowship)Fondazione Fronzaroli (postdoctoral fellowship)National Institutes of Health: R21 NS127432 Eunice Kennedy Shriver National Institute of Child Health and Human Development: P50 HD105353 National Institutes of Health: AG046495
This work was supported by grants from Fondazione Telethon to M.D. (GGP14147 and GGP19099) and grants from the Charcot- Marie-Tooth Association (CMTA) to M.D. and J.S., Fondazione Veronesi (postdoctoral fellowship to T.T.), a Fondazione Fronzaroli (postdoctoral fellowship to F.A.V.), and a grant from the National Institutes of Health to J.S. (R21 NS127432 provided by NINDS), a core grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to the Waisman Center (P50 HD105353) and the National Institutes of Health (AG046495 to J.W.K. and R.L.W.).
- Language
- English
- Electronic publication date
- 02/21/2025
- Date published
- 06/03/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984790993002771
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