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

2021 ◽  
Author(s):  
Päivi Lindholm ◽  
Mart Saarma
Keyword(s):  
Er Stress ◽  
Neurotrophic Factor ◽  
Early Stage ◽  
Dopamine Neurons ◽  
Enteric Neurons ◽  
Experimental Medicine ◽  
Functional Changes ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
The Brain ◽  
Cerebral Dopamine

AbstractMidbrain 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.

scholarly journals Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding

2019 ◽  
Author(s):  
Leonardo Maciel ◽  
Dahienne Ferreira de Oliveira ◽  
Fernanda Mesquita ◽  
Hercules Antônio da Silva Souza ◽  
Leandro Oliveira ◽  
...  
Keyword(s):  
Er Stress ◽  
Receptor Binding ◽  
Neurotrophic Factor ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Calcium Transient ◽  
New Family ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
Kdel Receptor ◽  
Cerebral Dopamine

AbstractCDNF (Cerebral Dopamine Neurotrophic Factor) belongs to a new family of NF, which presents several beneficial activities beyond the brain. Little is known about CDNF in the cardiac context. Herein we investigate CDNF effects in cardiomyocytes under endoplasmic reticulum (ER)-stress and in whole rat hearts subjected to ischemia/reperfusion (I/R). We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. CDNF protects human and mouse cardiomyocytes against ER-stress by restoring the calcium transient, and isolated heart against I/R injuries by reducing the infarct area and avoiding mitochondrial impairment. This protection is abrogated by wortmannin (PI3K-inhibitor) or by heptapeptides containing KDEL sequence, which block KDEL-receptor. These data suggest that CDNF induces cardioprotection via KDEL receptor binding and PI3K/AKT activation. This is the first study to propose CDNF as a cardiomyokine and to unravel the receptor and signaling pathway for this interesting family of NF.

scholarly journals Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

2022 ◽  
Vol 17 (4) ◽  
pp. 854
Author(s):  
Daniel Martinez-Fong ◽  
ManuelA Fernandez-Parrilla ◽  
David Reyes-Corona ◽  
YazminM Flores-Martinez ◽  
Rasajna Nadella ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopamine Neurons ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
6 Hydroxydopamine ◽  
Cerebral Dopamine

scholarly journals Cerebral Dopamine Neurotrophic Factor regulates multiple neuronal subtypes and behavior

2019 ◽  
Author(s):  
Yu-Chia Chen ◽  
Diego Baronio ◽  
Svetlana Semenova ◽  
Shamsiiat Abdurakhmanova ◽  
Pertti Panula
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Underlying Mechanism ◽  
Social Attraction ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
Shoaling Behavior ◽  
The Brain ◽  
Cerebral Dopamine

AbstractCerebral Dopamine Neurotrophic Factor (CDNF) protects dopaminergic neurons against toxic damage in the rodent brain, and is in clinical trials to treat Parkinson’s disease patients. Yet the underlying mechanism is poorly understood. To examine its mode of action and significance, we examined the development of neurotransmitter systems from larval to adult mutant zebrafish lacking cdnf. Although a lack of cdnf did not affect overall brain dopamine levels, dopaminergic neuronal clusters showed significant abnormalities. The number of histamine neurons that surround the dopaminergic neurons was significantly reduced. Expression of tyrosine hydroxylase 2 in the brain was elevated in cdnf mutants throughout their lifespan. There were abnormally few GABA neurons in the hypothalamus in the mutant larvae, and expression of glutamate decarboxylase was reduced throughout the brain. cdnf mutant adults showed a range of behavioral phenotypes, including increased sensitivity to pentylenetetrazole-induced seizures. Shoaling behavior of mutant adults was abnormal, and they did not display social attraction to conspecifics. CDNF plays a profound role in shaping the neurotransmitter circuit structure, seizure susceptibility, and complex behaviors in zebrafish. These findings are informative for dissecting the diverse functions of this poorly understood factor in human conditions related to Parkinson’s disease and complex behaviors

scholarly journals Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
P. Stepanova ◽  
V. Srinivasan ◽  
D. Lindholm ◽  
M. H. Voutilainen
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Quinolinic Acid ◽  
Neurotrophic Factor ◽  
Striatal Neurons ◽  
In Vivo Models ◽  
Cerebral Dopamine Neurotrophic Factor ◽  
Cerebral Dopamine

Abstract Huntington’s disease (HD) is a neurodegenerative disorder with a progressive loss of medium spiny neurons in the striatum and aggregation of mutant huntingtin in the striatal and cortical neurons. Currently, there are no rational therapies for the treatment of the disease. Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) properties, protecting and restoring the function of dopaminergic neurons in animal models of PD more effectively than other NTFs. CDNF is currently in phase I–II clinical trials on PD patients. Here we have studied whether CDNF has beneficial effects on striatal neurons in in vitro and in vivo models of HD. CDNF was able to protect striatal neurons from quinolinic acid (QA)-induced cell death in vitro via increasing the IRE1α/XBP1 signalling pathway in the ER. A single intrastriatal CDNF injection protected against the deleterious effects of QA in a rat model of HD. CDNF improved motor coordination and decreased ataxia in QA-toxin treated rats, and stimulated the neurogenesis by increasing doublecortin (DCX)-positive and NeuN-positive cells in the striatum. These results show that CDNF positively affects striatal neuron viability reduced by QA and signifies CDNF as a promising drug candidate for the treatment of HD.

Sign in / Sign up

Export Citation Format

Share Document