CDNF and MANF regulate ER stress in a tissue-specific manner

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.

CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival

“…For example, an ER stress-induced increase in CDNF expression was detected in cardiomyocytes [ 65 ], but not in an osteosarcoma-derived cell line [ 26 ]. Moreover, a recent study showed that while CDNF and MANF show redundancy in some mouse tissues, they still have some different target tissues where they exert their function as ER stress regulators [ 28 ]. The results of our study, for the first time, revealed that endogenous CDNF levels were increased in response to ER stress-inducing intraperitoneal injections of tunicamycin in the mouse liver and kidney in vivo.…”

“…Several lines of evidence suggest that MANF can regulate UPR signaling [ 24 , 25 , 26 ]. It has been suggested that CDNF, too, is participating in the regulation of UPR signaling [ 27 , 28 , 29 ]. CDNF downregulated UPR markers in cultured DA neurons under ER stress and in the rat striatum in a 6-OHDA model of PD [ 27 ].…”

UPR Responsive Genes Manf and Xbp1 in Stroke

“…Interestingly, MANF is an UPR activated gene ( Tseng et al, 2017 ; Hartman et al, 2019 ; Jäntti and Harvey, 2020 ; Pakarinen et al, 2020 , 2022 ). MANF works under reductive ER stress in the heart as well ( Arrieta et al, 2020 ).…”

“…Extracellular levels of MANF also increase in response to cell death. In addition, the action and secretion of MANF could vary in different cells, as MANF (and CDNF) regulates ER homeostasis in a tissue-specific manner ( Pakarinen et al, 2022 ).…”

“…Furthermore, our MANF KO studies have shown a clear link between MANF and XBP1. MANF ablation causes prolonged UPR activation, and sXBP1 is highly upregulated in MANF KO tissues ( Pakarinen et al, 2020 , 2022 ). In comparison, neuron-specific MANF expression in vivo improved the outcome in the 6-OHDA toxin model of Parkinson’s disease by reducing the levels of p-eIF2a, ATF4, CHOP, XBP1s, GRP78, and ATF6α ( Hao et al, 2017 ).…”