Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

Abstract

Midbrain dopamine neurons deteriorate in Parkinson’s disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf−/− mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.

CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival

“…The distinct functions of the N-terminal nucleotide-binding domain (NBD) and the C-terminal substrate-binding domain (SBD) of GRP78 have been well described [ 56 ]. Similarly, the two domains of CDNF have been proposed to have distinct roles in the molecular biology of CDNF, although experimental data about these possible roles are still lacking [ 7 , 9 , 57 ].…”

“…Although CDNF has been tested in phase I-II clinical trials in Parkinson’s disease patients [ 8 , 9 ], the molecular mechanism of its action is still under investigation. Despite recent publications associating CDNF with the UPR [ 27 , 29 ], the roles for CDNF in ER stress in vitro and in vivo have not been widely explored.…”

“…In animal models of different neuronal pathologies, CDNF and MANF promote the survival of various neuronal populations yet are structurally and functionally clearly distinct from classical neurotrophic factors (NTFs) [ 7 , 8 , 9 ]. NTFs such as proteins from the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) and neurotrophins are secreted proteins that exert their survival-promoting effects by binding to the extracellular domains of their cognate plasma membrane receptors, thus activating intracellular signaling pathways, eventually leading to diverse cellular outcomes [ 10 , 11 ].…”

UPR Responsive Genes Manf and Xbp1 in Stroke

“…MANF and cerebral dopamine neurotrophic factor (CDNF) are proteins with pleiotropic effects on various disease models ( Lindahl et al, 2017 ; Albert and Airavaara, 2019 ; Jäntti and Harvey, 2020 ; Lindholm and Saarma, 2021 ) and form together a family of proteins (amino acid identity is 59%) ( Lindholm et al, 2007 ). MANF was originally discovered and named ARMET (arginine-rich, mutated in early-stage tumor) ( Shridhar et al, 1996 ) but was subsequently renamed MANF when the protein was first successfully isolated from a mesencephalic astrocyte cell line, and its neurotrophic properties were reported using dopaminergic neuronal cultures ( Petrova et al, 2003 ).…”

Exploring the Pharmacological Potential of Metformin for Neurodegenerative Diseases

“…Some studies have shown that neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) upregulate tyrosine hydroxylase (TH), improve movement disorders and provide neuroprotection in animal models of Parkinson’s disease ( Gash et al, 2005 ; Lindholm and Saarma, 2021 ). Katila et al (2020) indicated that by promoting the phosphorylation of tyrosine hydroxylase (TH), metformin simultaneously increases brain-derived and glial cell-derived neurotrophic factor (GDNF), thereby activating the cell survival signaling pathways.…”