Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo

Autor: Albert, Katrina, Raymundo, Diana P., Panhelainen, Anne, Eesmaa, Ave, Shvachiy, Liana, Araujo, Gabriela R., Chmielarz, Piotr, Yan, Xu, Singh, Aastha, Cordeiro, Yraima, Palhano, Fernando L., Foguel, Debora, Luk, Kelvin C., Domanskyi, Andrii, Voutilainen, Merja H., Huttunen, Henri J., Outeiro, Tiago F., Saarma, Mart, Almeida, Marcius S., Airavaara, Mikko
Přispěvatelé: Regenerative Neuroscience, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Divisions of Faculty of Pharmacy, Helsinki One Health (HOH), Neuroscience Center, Biosciences, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Henri Juhani Huttunen / Principal Investigator, Mart Saarma / Principal Investigator
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Popis: A molecular hallmark in Parkinson's disease (PD) pathogenesis are a-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of alpha-synuclein. Here, we investigated the effects of CDNF on alpha-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with alpha-synuclein with a KD = 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 alpha-synuclein fibrils and induces the formation of insoluble phosphorylated alpha-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with a-synuclein fibrils, though it did not reduce the number of phosphorylated alpha-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 a-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.
Databáze: OpenAIRE