Effects of CDNF on 6-OHDA-induced apoptosis in PC12 cells via modulation of Bcl-2/Bax and caspase-3 activation

Abstract

Progressive dopamine neuron degeneration in the substantia nigra pars compacta is considered the most prominent pathological characteristic of Parkinson's disease (PD). Currently, there is no cure, but only the capability to relieve the symptoms of PD. The conserved dopamine neurotrophic factor (CDNF) protects and rescues dopamine neurons in vivo. However, the molecular function of CDNF in PD remains unclear. In present study, we investigated the role and intrinsic mechanism of CDNF in preventing and reversing rat pheochromocytoma (PC12) cells from apoptosis induced by 6-hydroxydopamine (6-OHDA). We demonstrate that 6-OHDA induces cell death in PC12 cells, but that CDNF attenuates this effect in a dose-dependent manner. Further study shows that upregulation of the Bcl-2/Bax ratio and downregulation of caspase-3 activity are observed in a dose-dependent manner upon pre-treatment or post-treatment with CDNF, suggesting a pathway of regulation of apoptosis by CDNF. These data demonstrate that CDNF prevents the apoptosis of PC12 cells induced by 6-OHDA by modulating Bcl-2/Bax and caspase-3 activation.

Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson’s disease: Involvement of antioxidative enzymes induction

“…These results suggested that the neuroprotection of CA is associated with inhibition of the 6-OHDA-mediated the Bcl-2/Bax ratio reduction and apoptosis induction. Consistent with other studies, Mei et al indicated that neurotrophic factor prevented the apoptosis of PC12 cells induced by 6-OHDA through upregulation of Bcl-2/Bax ratio and downregulation of caspase-3activity [38]. Luteolin protected PC12 cells against 6-OHDA-induced apoptosis via suppressing the induction of Bax, inhibiting the reduction of Bcl-2, and reducing the induction of Bax/Bcl-2 ratio [39].…”

The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers

“…Using steady-state tryptophan intrinsic fluorescence polarization (69) and far dot blotting (70) we did not find any evidence of interaction among CDNF and neither monomeric nor oligomeric ␣-synuclein (data not shown). Notwithstanding, other possible mechanisms of action for CDNF might include: 1) binding to a transmembrane receptor, like other neurotrophic factors, activating survival pathways that surpasses the toxic effect of ␣-synuclein; 2) stimulating the cellular clearance pathways such as chaperone-mediated autophagy; and 3) inhibiting apoptosis by interaction with BAX via its Ku70-like active site (15,18). Because CDNF has two domains, it can use at least two mechanisms to protect dopaminergic neurons against toxic prefibrillar oligomers of ␣-synuclein.…”

“…Accordingly, cytoplasmic injection of either full-length MANF or its C-terminal domain alone leads to an inhibition of Bax-dependent apoptosis in mouse superior cervical ganglion neurons, which suggests that this NTF possesses an intracellular mode of action (15). Indeed, exogenously applied CDNF is able to prevent apoptosis in PC12 cells by modulating Bcl-2/Bax and caspase-3 activation (18). MANF also contains a functional KDEL endoplasmic reticulum retention signal at its C terminus, which binds to KDEL receptors both intracellularly and on the cell membrane (19).…”

Key subdomains in the C-terminal of cerebral dopamine neurotrophic factor regulate the protein secretion

“…In the apoptotic cells, Ku70 dissociates from Bax, thereby Bax is activated and trigger the mitochondrial cell death pathway [13,14]. There is reported that CDNF can prevent the apoptosis of PC12 cells induced by 6-OHDA by modulating Bcl-2/Bax and caspase-3 activation [15]. Strikingly, the C-terminal domain of MANF and C-terminal domain of Ku70 share a similar epitope, located at the beginning of the α7 [7].…”