AUTHOR=Scordino Miriana , Stepanova Polina , Srinivasan Vignesh , Pham Dan Duc , Eriksson Ove , Lalowski Maciej , Mudò Giuseppa , Di Liberto Valentina , Korhonen Laura , Voutilainen Merja H. , Lindholm Dan TITLE=CNPY2 protects against ER stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington’s disease JOURNAL=Frontiers in Molecular Neuroscience VOLUME=Volume 17 - 2024 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1473058 DOI=10.3389/fnmol.2024.1473058 ISSN=1662-5099 ABSTRACT=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, while 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 CNPY2-immunopositive 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.