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

Stepanova, Polina; Srinivasan, Vignesh; Lindholm, Dan; Voutilainen, Merja H.

doi:10.1038/s41598-020-75439-1

Cited by 17 publications

(12 citation statements)

References 67 publications

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“…CDNF was also shown to have beneficial effects in animal models of Alzheimer’s disease [ 120 ], amyotrophic lateral sclerosis [ 121 ], and Huntington’s disease [ 122 ]. However, further studies are required to confirm these exciting results.…”

Section: Introductionmentioning

confidence: 99%

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

Lindholm

Saarma

2021

Mol Psychiatry

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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.

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Section: Introductionmentioning

confidence: 99%

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

Lindholm

Saarma

2021

Mol Psychiatry

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“…Quinolinic acid neurotoxicity is also thought to play a role in the further pathogenesis of Parkinson’s disease [ 66 ]. Thus, studies have shown that quinolinic acid or its Fe-chelate is involved in degeneration of the dopaminergic neurons in the substantia nigra (SN) of Parkinson’s disease patients [ 67 ]. SN degeneration combined with iron deposition is one of the key characteristics of this disease [ 68 , 69 ].…”

Section: Quinolinic Acidmentioning

confidence: 99%

The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

et al. 2022

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Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.

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“…The diffusion of CDNF in brain is more prolonged and distributed widely than that of other NTFs, and the half-life is approximately 5.5 h 23 , 36 , 37 . Previous studies have demonstrated that CDNF exerts neuroprotective and neurorestorative effects in rodent and non-human primate models of PD 27 , 37 – 39 .…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, we demonstrated that a single intrastriatal injection of CDNF has a positive effect in the quinolinic acid (QA)-toxin model of HD 23 . CDNF improved motor behavior and increased the NeuN- and doublecortin-immunopositive cell populations in vivo and protected striatal neurons after QA toxin-induced cell death in vitro.…”

Section: Introductionmentioning

confidence: 99%

Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease

Stepanova

Kumar

Cavonius

et al. 2023

Sci Rep

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Huntington’s disease (HD) is a progressive inherited neurological disease characterized by the degeneration of basal ganglia and the accumulation of mutant huntingtin (mHtt) aggregates in specific brain areas. Currently, there is no treatment for halting the progression of HD. Cerebral dopamine neurotrophic factor (CDNF) is a novel endoplasmic reticulum located protein with neurotrophic factor properties that protects and restores dopamine neurons in rodent and non-human primate models of Parkinson’s disease. Our recent study showed that CDNF improves motor coordination and protects NeuN positive cells in a Quinolinic acid toxin rat model of HD. Here we have investigated the effect of chronic intrastriatal CDNF administration on behavior and mHtt aggregates in the N171-82Q mouse model of HD. Data showed that CDNF did not significantly decrease the number of mHtt aggregates in most brain regions studied. Notably, CDNF significantly delayed the onset of symptoms and improved motor coordination in N171-82Q mice. Furthermore, CDNF increased BDNF mRNA level in hippocampus in vivo in the N171-82Q model and BDNF protein level in cultured striatal neurons. Collectively our results indicate that CDNF might be a potential drug candidate for the treatment of HD.

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

Cited by 17 publications

References 67 publications

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

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

The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease

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