Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo
Katrina Albert, Diana Pelizzari Raymundo, Anne Panhelainen, Ave Eesmaa, Liana Shvachiy, Gabriela Rocha de Araújo, Piotr Chmielarz, Yan Xu, Aastha Singh, Yraima Cordeiro, Fernando L. Palhano, Débora Foguel, Kelvin C. Luk, Andrii Domanskyi, Merja H. Voutilainen, Henri J. Huttunen, Tiago F. Outeiro, Märt Saarma, Marcius S. Almeida, Mikko Airavaara
Abstract
= 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils and induces the formation of insoluble phosphorylated α-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with α-synuclein fibrils, though it did not reduce the number of phosphorylated α-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with α-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.