Cerebral dopamine neurotrophic factor-deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice.

Abstract

Cerebral dopamine neurotrophic factor (CDNF) is neuroprotective for nigrostriatal dopamine neurons and restores dopaminergic function in animal models of Parkinson's disease (PD). To understand the role of CDNF in mammals, we generated CDNF knockout mice (Cdnf-/-), which are viable, fertile, and have a normal life-span. Surprisingly, an age-dependent loss of enteric neurons occurs selectively in the submucosal but not in the myenteric plexus. This neuronal loss is a consequence not of increased apoptosis but of neurodegeneration and autophagy. Quantitatively, the neurodegeneration and autophagy found in the submucosal plexus in duodenum, ileum and colon of the Cdnf-/- mouse are much greater than in those of Cdnf+/+ mice. The selective vulnerability of submucosal neurons to the absence of CDNF is reminiscent of the tendency of pathological abnormalities to occur in the submucosal plexus in biopsies of patients with PD. In contrast, the number of substantia nigra dopamine neurons and dopamine and its metabolite concentrations in the striatum are unaltered in Cdnf-/- mice; however, there is an age-dependent deficit in the function of the dopamine system in Cdnf-/- male mice analyzed. This is observed as D-amphetamine-induced hyperactivity, aberrant dopamine transporter function, and as increased D-amphetamine-induced dopamine release demonstrating that dopaminergic axon terminal function in the striatum of the Cdnf-/- mouse brain is altered. The deficiencies of Cdnf-/- mice, therefore, are reminiscent of those seen in early stages of Parkinson's disease.

• Authors: Maria Lindahl, Alcmène Chalazonitis, Erik Palm, Emmi Pakarinen, Tatiana Danilova, Tuan D Pham, Wanda Setlik, Meenakshi Rao, Vootele Võikar, Jatta Huotari, Jaakko Kopra, Jaan-Olle Andressoo, Petteri T Piepponen, Mikko Airavaara, Anne Panhelainen, Michael D Gershon, Mart Saarma
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 134 Pg. 104696 (02 2020) ISSN: 1095-953X [Electronic] United States
• PMID: 31783118 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Nerve Growth Factors
• cdnf protein, mouse
• Dopamine

Topics

• Animals
• Apoptosis
• Autophagy
• Brain (pathology, physiology)
• Dopamine (metabolism)
• Enteric Nervous System (pathology, physiopathology)
• Female
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Growth Factors (genetics, physiology)
• Neurons (pathology, physiology)