Cerebral dopamine neurotrophic factor–deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice

Lindahl, Maria; Chalazonitis, Alcmène; Palm, Erik; Pakarinen, Emmi; Danilova, Tatiana; Pham, Tuan D.; Setlik, Wanda; Rao, Meenakshi; Võikar, Vootele; Huotari, Jatta; Kopra, Jaakko; Andressoo, Jaan‐Olle; Piepponen, Petteri; Airavaara, Mikko; Panhelainen, Anne; Gershon, Michael D.; Saarma, Märt

doi:10.1016/j.nbd.2019.104696

Cited by 36 publications

(82 citation statements)

References 87 publications

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“…Therefore, in the future, it will be important to quantify the number of synapses (DeKosky and Scheff, 1990) and examine individual synapses of dopamine neurons in MANFdeficient mice using highly sensitive technologies, such as mass synaptometry (Gajera et al, 2019). Furthermore, changes in dopamine transmission at the synapses can also occur without dopamine neuron loss as shown in CDNF KO mice (Lindahl et al, 2020). Despite the unchanged response to amphetamine, detailed investigation of the dopamine neurotransmission in MANF-deficient mice would be justified in the future.…”

Section: Discussionmentioning

confidence: 99%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a

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Section: Discussionmentioning

confidence: 99%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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“…CDNF is a neurotrophic factor that can protect neurons and bind to GRP78. Its expression is correlated with that of GRP78 [ 21 – 25 ]. Activation of UPR requires the activation of GRP78 [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Congrong Shujing Granule‐Induced GRP78 Expression Reduced Endoplasmic Reticulum Stress and Neuronal Apoptosis in the Midbrain in a Parkinson’s Disease Rat Model

Yang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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The main pathological changes inherent in Parkinson’s disease (PD) are degeneration and loss of dopamine neurons in the midbrain and formation of Lewy bodies. Many studies have shown that the pathogenesis of PD is closely related to endoplasmic reticulum (ER) oxidative stress. This study combined various traditional Chinese medicines to prepare Congrong Shujing granules (CSGs). The optimal dose combination of the ingredients was identified by experimental intervention in SH-SY5Y cells in vitro. A PD rat model was established by intraperitoneal injection of rotenone sunflower oil emulsion. The suspension tests were performed on the 14th day after modeling and also on the 14th day after CSG intervention (5.88 g/kg, 11.76 g/kg, and 23.52 g/kg). We evaluated the changes in motor function and the expression of neuronal cell functional marker proteins, ER stress (ERS) marker proteins, and apoptosis-related pathway proteins of neuronal cells. Changes in cellular ultrastructure were observed by electron microscopy. Our results showed that CSG treatment lengthened the duration of PD rats’ gripping to the wire. 78 kDa glucose-regulated protein (GRP78) expression in the substantia nigra was significantly upregulated in the middle- and high-dose CSG groups after 14 days of treatment compared with the model group. The expression of the key dopaminergic neuron functional enzyme tyrosine hydroxylase (TH) and cerebral dopamine neurotrophic factor (CDNF) was elevated. The expression of c-Jun N-terminal kinase (JNK) and phosphorylated c-Jun decreased, and cell apoptosis was significantly reduced. Compared with the model group, the treatment groups had fewer ER fragmentation and degranulation (ribosome shedding) and abundant ER and mitochondria suggesting that CSG reduced ER stress and neuronal apoptosis in the midbrain of a PD rat model by inducing the expression of molecular chaperone GRP78.

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“…Intra-assay precision was determined by measuring three samples with varying concentrations of recombinant mouse CDNF in replicates of ten on different parts of a plate, while inter-assay precision was determined by running three samples with different recombinant CDNF concentrations in duplicate in a minimum of five independent assays. Cdnf -/- 60 mouse tissue lysates were negative on CDNF ELISA, implicating high specificity to the analyte.…”

Section: Methodsmentioning

confidence: 99%

CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

Lorenzo

Lüningschrör

Nam

et al. 2020

Preprint

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One sentence summaryCerebral dopamine neurotrophic factor (CDNF) was found to substantially attenuate amyotrophic lateral sclerosis (ALS)-associated pathology in three preclinical rodent models via modulation of the endoplasmic reticulum (ER) stress, highlighting its potential therapeutic use in this motor neuron disease. AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily afflicting motor neurons (MNs) of the spinal cord, brainstem, and motor cortex, leading to paralysis and eventually death within 3 to 5 years of diagnosis. No cure or effective therapy to halt ALS progression is available. The role of chronic endoplasmic reticulum (ER) stress in the pathophysiology of ALS, as well as a potential drug target, has received increasing attention. Here, we investigated the therapeutic effect of the ER resident protein cerebral dopamine neurotrophic factor (CDNF) in preclinical models of ALS harboring different genetic mutations. We identify that intracerebroventricular (i.c.v.) administration of CDNF significantly halts the progression of the disease and improves motor behavior in TDP43-M337V and SOD1-G93A rodent models of ALS.CDNF rescues MNs in vitro and in vivo from ER stress associated cell death and its beneficial effect is independent of genetic disease etiology. Notably, CDNF regulates the unfolded protein response (UPR) initiated by transducers IRE1α, PERK, and ATF6, thereby enhancing MN survival. Thus, CDNF holds great promise for the design of new rational treatments for ALS.

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Cerebral dopamine neurotrophic factor–deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice

Cited by 36 publications

References 87 publications

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Congrong Shujing Granule‐Induced GRP78 Expression Reduced Endoplasmic Reticulum Stress and Neuronal Apoptosis in the Midbrain in a Parkinson’s Disease Rat Model

CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

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