Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington\u2019s disease

P Stepanova,D Lindholm,M H Voutilainen,V Srinivasan

doi:10.1038/s41598-020-75439-1

P Stepanova, D Lindholm + Show 2 more

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https://doi.org/10.1038/s41598-020-75439-1

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Journal: Scientific Reports	Publication Date: Nov 5, 2020
Citations: 16	License type: open-access

Affiliation: University of Helsinki, Minerva Foundation

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.

Highlights

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
We observed a wide Cerebral dopamine neurotrophic factor (CDNF) diffusion in the striatum, and the substantia nigra pars compacta (SNpc) 2 h after injection. This is in line with the previous data showing that CDNF is retrogradely transported from the striatum to the SNpc[39,51]
(one-way ANOVA followed by Bonferroni’s post hoc test, p < 0.005) as well as the level of spliced XBP1 (XBP1s) protein (Fig. 7B,C). Together these results show that CDNF increases the viability of striatal neurons in culture and counteracts the deleterious effects induced by the neurotoxin quinolinic acid (QA)

Summary

Introduction

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. Neurotrophic factors are secretory proteins that promote the survival and differentiation of neurons both during development and in different disease conditions and influence different intracellular signalling pathways that counteract the process of neuronal d egeneration[16] Different neurotrophic factors, such as BDNF, ciliary neurotrophic factor (CNTF), insulin-like growth factor-I (IGF-I), nerve growth factor (NGF), neurturin (NRTN) and glial cell line-derived neurotrophic factor (GDNF) have demonstrated a protective role in genetic and neurotoxin models of HD including the 2,3‐pyridine dicarboxylic acid (quinolinic acid, QA) and 3-nitropropionic acid (3-NP) m odels[17,18,19,20,21,22,23]. Injections of QA into the striatum of rodents or primates has shown to produce similar neurochemical features as seen in HD patients[28,29], making it a useful tool to study the neuropathology of HD30

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