Cerebral Dopamine Neurotrophic Factor Reduces α-Synuclein Aggregation and Propagation and Alleviates Behavioural Alterations in vivo.

Abstract A molecular hallmark in Parkinson’s Disease (PD) pathogenesis are α-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 α-synuclein. Here, we investigated the effects of CDNF on α-synuclein aggregation in vitro and in vivo. We found that CDNF interacts with α-synuclein with a Kd = 28 ± 6 nM and reduces its auto-association. Using NMR spectroscopy, we identified interaction sites on the structure of CDNF. 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 behaviour appear not to be related to amount 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 behavioural alterations, provide novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.