Although cerebral dopamine neurotrophic factor (CDNF) is considered a “neurotrophic factor (NF),” its mechanism of action differs from classic NFs that increase cell survival through intracellular signaling. CDNF is located in the endoplasmic reticulum (ER), is secreted in response to ER stress, and reduces ER stress after internalization. 1 Voutilainen M.H. Arumäe U. Airavaara M. Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015; 589: 3739-3748 Crossref PubMed Scopus (54) Google Scholar In this issue of Molecular Therapy, Albert et al. 2 Albert K. Raymundo D.P. Panhelainen A. Eesmaa A. Shvachiy L. Araújo G.R. Chmielarz P. Yan X. Singh A. Cordeiro Y. et al. Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo. Mol. Ther. 2021; 29: 2821-2840 Abstract Full Text Full Text PDF Scopus (8) Google Scholar demonstrate that CDNF directly binds to α-synuclein in vitro and in vivo. They further show that CDNF reduced α-synuclein aggregation as well as internalization of α-synuclein preformed fibrils (PFFs) in neuronal cultures. Delivery of CDNF alleviated behavioral deficits induced by α-synuclein PFFs. Interestingly, in this model, the behavioral abnormalities appeared in the absence of DA neuronal cell death. The data suggest that CDNF can reverse neuronal dysfunction at a very early stage, before the appearance of evident neurodegeneration. Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivoAlbert et al.Molecular TherapyApril 30, 2021In BriefAiravaara, Almeida, and colleagues show that CDNF, a therapeutic protein that is in clinical trials for Parkinson’s disease, interacts with α-synuclein. α-synuclein aggregates to form Lewy bodies, often observed in postmortem brains of Parkinson’s patients. They show that this CDNF-α-synuclein interaction modifies its aggregation and may lead to functional recovery in their animal model. Full-Text PDF Open Access