Abstract
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) display cytoprotective effects in animal models of neurodegenerative diseases. These endoplasmic reticulum (ER)-resident proteins belong to the same protein family and function as ER stress regulators. The relationship between CDNF and MANF function, as well as their capability for functional compensation, is unknown. We aimed to investigate these questions by generating mice lacking both CDNF and MANF. Results showed that CDNF-deficient Manf−/− mice presented the same phenotypes of growth defect and diabetes as Manf−/− mice. In the muscle, CDNF deficiency resulted in increased activation of unfolded protein response (UPR), which was aggravated when MANF was ablated. In the brain, the combined loss of CDNF and MANF did not exacerbate UPR activation caused by the loss of MANF alone. Consequently, CDNF and MANF deficiency in the brain did not cause degeneration of dopamine neurons. In conclusion, CDNF and MANF present functional redundancy in the muscle, but not in the other tissues examined here. Thus, they regulate the UPR in a tissue-specific manner.
Highlights
Genetic compensation refers to changes at the gene expression level that can compensate for the loss of function of another gene
Measurements of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein levels from sera of WT and Cdnf−/− mice showed that female Cdnf−/− mice had higher MANF protein levels (3.26 ± 0.2 ng/ml) in their sera when compared with female WT mice (2.14 ± 0.3 ng/ml) (Fig. 1c)
Preliminary data suggest an increase in MANF levels in Cdnf−/− male mice compared to WT male mice
Summary
Genetic compensation refers to changes at the gene expression level that can compensate for the loss of function of another gene. Proteins with similar structures or functions can compensate for each other. Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are homologous proteins with a similar two-domain structure distinct from other neurotrophic factors [2]. They have a signal sequence that directs them cotranslationally to the endoplasmic reticulum (ER) and secretory pathway, and an ER retention signal that resembles the canonical KDEL sequence regulating their secretion and retrieval to the ER. CDNF and MANF have cytoprotective effects in different animal disease models, such as Parkinson’s disease, ischemic stroke, and spinocerebellar ataxia [5,6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
