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

Abstract

Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson’s disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function. We used tunicamycin to induce ER stress in mice in vivo and used cultured primary neurons and found that CDNF expression is regulated by ER stress in vivo and that the involvement of UPR pathways is important for the neuroprotective function of CDNF. Moreover, we used AP-MS and BiFC to perform the first interactome screening for CDNF and report novel binding partners of CDNF. These findings allowed us to hypothesize that CDNF protects neurons from ER-stress-inducing agents by modulating UPR signaling towards cell survival outcomes.

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

“…SBD, substrate binding domain. (B) MANF and CDNF are members of the ER-localized multiprotein complex of chaperones, as demonstrated in affinity-purification mass spectrometry experiments (20,145). (C) MANF regulates IRE1α signaling under ER stress.…”

“…Unlike classical NTFs, survival-promoting effects of exogenous CDNF and MANF on naïve dopamine neurons and other types of naïve neurons seem to be very low or possibly even non-existent (12,20,145). When CDNF was added to the culture media, it did not promote the survival of naïve primary SCG neurons, motoneurons, or DRG neurons in vitro, differently from the respective control NTFs, i.e., nerve growth factor, ciliary neurotrophic factor, and GDNF (12).…”

“…MANF binding inhibits IRE1α phosphorylation, oligomerization, and downstream signaling, preventing cell death (119). takes place between the C-terminal domain of CDNF and the NBD of GRP78, which indicates that CDNF may function as a cofactor of GRP78 (20). However, the exact interaction interface between CDNF and GRP78 proteins remains to be defined.…”

“…CDNF is a vertebrate-specific paralog of MANF (12). In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) (19,20), where they regulate protein homeostasis and ER stress-induced unfolded protein response (UPR) signaling (21)(22)(23)(24)(25). As a potential therapeutic factor for dopamine neurons, CDNF was tested in Phase I-II clinical trials in 17 PD patients, where it was shown to be safe and well tolerated (26,27).…”

Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease

“…Previous data on the effects of CDNF on ER stress markers support the hypothesis of direct regulation of UPR pathways by CDNF 22 , 33 . Moreover, recent data showed that CDNF interacts with the main ER chaperone Bip (as known as GRP78) 34 , is upregulated and secreted in response to experimental ER stress, and protects cells from ER stress-induced cell death both in vitro and in vivo 24 , 35 .…”