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

Mol Ther. 2021 Sep 1;29(9):2821-2840. doi: 10.1016/j.ymthe.2021.04.035. Epub 2021 May 1.


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 directly interacts with α-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 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.

Keywords: CDNF; MANF; Parkinson’s disease; cerebral dopamine neurotrophic factor; mesencephalic astrocyte-derived neurotrophic factor; pre-formed α-synuclein fibrils; protein aggregation; synucleinopathy; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Disease Models, Animal
  • Dopamine / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Models, Molecular
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / metabolism*
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology*
  • Phosphorylation
  • Primary Cell Culture
  • Protein Aggregates
  • Protein Binding
  • Protein Conformation
  • Rats
  • Substantia Nigra / metabolism*
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / metabolism*


  • CDNF protein, human
  • Nerve Growth Factors
  • Protein Aggregates
  • SNCA protein, human
  • alpha-Synuclein
  • Dopamine