Non-invasive peripheral delivery of CDNF fragment protects neurons in models of Parkinsons and ALS
Yu, L.; Viljakainen, T.; Beckett, L.; Nam, J.; Hyysalo, A.; Luningschror, P.; Albert, K.; Koppinen, T. K.; Hyvarinen, T.; Tossavainen, H.; Hellman, M.; Airavaara, M.; Sendtner, M.; Permi, P.; Lindholm, P.; Saarma, M.; Voutilainen, M. H.
Show abstract
Non-invasive delivery of brain therapeutics is a key challenge for treating neurodegenerative diseases. Here, we discovered a novel carboxy (C)-terminal fragment of cerebral dopamine neurotrophic factor (C-CDNF) that protects dopamine (DA) and motoneurons (MNs) in rodent models of Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). C-CDNF retains the same structure as CDNF and similarly to CDNF regulates cell stress pathways but unorthodoxly enters cultured neurons and passes through the blood-brain barrier. In vivo, intracranially or peripherally delivered C-CDNF improves motor deficits, protects DA neurons, and restores motor behavior in a rat model of PD. Subcutaneous C-CDNF also protects MNs and reduces microglial activation in an ALS model. Based on our findings, beginning C-CDNF treatment soon after diagnosis is anticipated to delay progression of PD and ALS, thereby improving treatment outcome. Thus, systemic delivery of C-CDNF should simplify the administration of protein-based therapeutics to patients while reducing treatment risk and financial burden for patients and families.
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