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

Päivi Lindholm,Mart Saarma

doi:10.1038/s41380-021-01394-6

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.

Highlights

Increased life expectancy and a growing aging population are leading to an increase in the incidence of age-related diseases, including Parkinson’s disease (PD) which affects 1% of population over 60 years of age [1], and with more than 6 million people diagnosed with PD globally [2]
While precise mechanisms of DA neuron death are unclear, increasing body of evidence suggests that protein aggregation, mitochondrial dysfunction, inflammation, and reduced growth factor levels are involved in the molecular pathogenesis of PD [6, 7]
Aggregation of misfolded α-synuclein, a major component of intraneuronal Lewy bodies, may possibly cause endoplasmic reticulum (ER) stress in DA neurons leading to neuronal death

Summary

INTRODUCTION

Increased life expectancy and a growing aging population are leading to an increase in the incidence of age-related diseases, including Parkinson’s disease (PD) which affects 1% of population over 60 years of age [1], and with more than 6 million people diagnosed with PD globally [2]. Future therapies should include interventions that slow down or prevent the degeneration and death of DA neurons, regenerate the remaining DA neurons and increase their functional activity They should alleviate non-motor symptoms of PD. CDNF and MANF have neurotrophic properties but they otherwise dramatically differ from other known NTFs (Table 1) They have a unique structure, mode of action and they can promote cellular protein homeostasis by regulating ER stress, regulate inflammation and support neuron survival in animal models of PD [22,23,24,25,26,27]. The C-terminal SAPdomain is important for the neuroprotective activity of MANF, since it can independently promote the survival of neurons in vitro [29] In their primary structure, CDNF/MANF proteins have eight cysteine residues with conserved spacing, which are important for the protein fold (Fig. 1B).

Polypeptide Number of amino acids in mature protein Active conformation

We still have very limited information about the effects of CDNF

ADDITIONAL INFORMATION