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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1473058

CNPY2 protects against ER Stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington´s Disease

Provisionally accepted
Miriana Scordino Miriana Scordino 1Polina Stepanova Polina Stepanova 2Vignesh Srinivasan Vignesh Srinivasan 3Dan D. Pham Dan D. Pham 3Ove Eriksson Ove Eriksson 3Maciej M. Lalowski Maciej M. Lalowski 3Giuseppa Mudò Giuseppa Mudò 4Valentina Di Liberto Valentina Di Liberto 4Laura Korhonen Laura Korhonen 5Merja H. Voutilainen Merja H. Voutilainen 2Dan Lindholm Dan Lindholm 1*
  • 1 Dept of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
  • 2 Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
  • 3 Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
  • 4 Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Sicily, Italy
  • 5 Department of Child and Adolescent Psychiatry, Linköping, Östergötland, Sweden

The final, formatted version of the article will be published soon.

    Canopy Homolog 2 (CNPY2) is an endoplasmic reticulum (ER) localized protein belonging to the CNPY gene family. We show here that CNPY2 is protective against ER stress induced by tunicamycin in neuronal cells. Overexpression of CNPY2 enhanced, whilst downregulation of CNPY2 using shRNA expression, reduced the viability of neuroblastoma cells after tunicamycin.Likewise, recombinant CNPY2 increased survival of cortical neurons in culture after ER stress.CNPY2 reduced the activating transcription factor 6 (ATF6) branch of ER stress and decreased the expression of CCAT/Enhancer-Binding Protein Homologous Protein (CHOP) involved in cell death.Immunostaining using mouse brain sections revealed that CNPY2 is expressed by cortical and striatal neurons and is co-expressed with the transcription factor, COUPTF-interacting protein 2 (CTIP2). In transgenic N171-82Q mice, as a model for Huntington´s disease (HD), the number of CNPY2immunopositive neurons was increased in the cortex together with CTIP2. In the striatum, however, the number of CNPY2 decreased at 19 weeks of age, representing a late-stage of pathology. Striatal cells in culture were shown to be more susceptible to ER stress after downregulation of CNPY2.These results demonstrate that CNPY2 is expressed by corticostriatal neurons involved in the regulation of movement. CNPY2 enhances neuronal survival by reducing ER stress and is a promising factor to consider in HD and possibly in other brain diseases.

    Keywords: upr, er stress, CNPY2, Ctip2, nerve cell viability, Huntington´s disease

    Received: 30 Jul 2024; Accepted: 29 Aug 2024.

    Copyright: © 2024 Scordino, Stepanova, Srinivasan, Pham, Eriksson, Lalowski, Mudò, Di Liberto, Korhonen, Voutilainen and Lindholm. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Dan Lindholm, Dept of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland

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