Journal: bioRxiv
Article Title: Non-invasive peripheral delivery of CDNF fragment protects neurons in models of Parkinson’s and ALS
doi: 10.1101/2025.02.09.637291
Figure Lengend Snippet: A) C-CDNF increased the survival of mouse dopamine (DA) neurons from growth factor deprivation in a dose- dependent manner. Mouse midbrain DA neurons were cultured with or without recombinant protein C-CDNF or N-CDNF (10-500 ng/ml) for 5 days. DA neurons were identified by TH immunostaining and expressed as % of cell survival in each condition compared to GDNF-treated neurons. Shown are the means ± SEM of 3-8 independent experiments per condition. B-C) C-CDNF can protect mouse DA neurons against 6-OHDA or thapsigargin-induced toxicity. DA neurons were treated with B) 15 µM 6-OHDA or C) 20 nM thapsigargin only, or toxin with the indicated growth factors. After three days, TH+ neurons were counted and expressed as % of cell survival in each condition compared to non-toxin treated neurons. Shown are the means of 5-8 experiments ± SEM D) C-CDNF increased the survival of MNs in a dose-dependent manner. MNs cultured 5 days in the presence of different concentrations of C-CDNF (5-500 ng/ml) BDNF/CNTF was used as a positive control. Mean ± SEM of 4 different experiments. E) C-CDNF protected MNs against thapsigargin induced toxicity in a dose-dependent manner. MNs were treated with thapsigargin (5 nM) for 24 h in the presence of different dose of C-CDNF (5-500 ng/ml). Mean ± SEM of 5 different experiments. F) C-CDNF 50 ng/ml rescued iPS cell-derived MNs from tunicamycin induced cell death. Mean ± SEM of 4-8 t experiments. G) C-CDNF protected commercially available iPSC-derived DA neurons against 6- OHDA induced toxicity. H) C-CDNF added to the cultured DA neurons decreased the expression levels of UPR transcripts upon 24 h thapsigargin (100 nM) induced ER stress as measured using qPCR (normalization to β-actin). Mean ± SEM of 11 experiments. I) Protective effect of C-CDNF against ER-stress is dependent on active IRE1α and PERK pathways. DA neurons were cultured with C-CDNF alone or in combination with 4µ8C, KIRA6 or GSK2606414 and with the treatment of thapsigargin (20 nM) for three days. TH-positive neurons were counted and expressed as % of non- toxin treated neurons. Shown are the means of 6 experiments ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001; one-way ANOVA followed by Sidak post hoc test in A–I.
Article Snippet: Recombinant CDNF protein, C-CDNF protein or C-CDNF peptide (100 ng/ml) and IRE1α inhibitors 4μ8C (10 μM) (HY-19707, MedChemExpress), KIRA6 (200nM) (HY-19708, MedChemExpress) or PERK inhibitor GSK2606414 (T2614, argetMol Chemicals) were added to the culture medium at the same time.
Techniques: Cell Culture, Recombinant, Immunostaining, Positive Control, Derivative Assay, Expressing
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