Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson’s disease

Dai, Ting‑Li; Zhang, Chan; Peng, Fang; Niu, Xue-Yuan; Hu, Ling; Zhang, Qiong; Huang, Ying; Chen, Ling; Zhang, Lei; Zhu, Weidong; Ding, Yu; Song, Ning‐Ning; Liao, Min

doi:10.3892/etm.2014.1745

Cited by 15 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several lines of evidence indicate that Wnt protein is involved in promoting development and survival of SNpc DAergic neurons through activating Wnt/β-catenin pathway [27][28][29][30][31][32][33] . Wnt1 activates canonical Wnt/β-catenin signaling pathway, and facilitates differentiation and survival of SN DAergic neurons 30,31 .…”

Section: Discussionmentioning

confidence: 99%

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

et al. 2020

View full text Add to dashboard Cite

Patients with familial type 17 of Parkinson’s disease (PARK17) manifest autosomal dominant pattern and late-onset parkinsonian syndromes. Heterozygous (D620N) mutation of vacuolar protein sorting 35 (VPS35) is genetic cause of PARK17. We prepared heterozygous VPS35D620N/+ knockin mouse, which is an ideal animal model of (D620N) VPS35-induced autosomal dominant PARK17. Late-onset loss of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons and motor deficits of Parkinson’s disease were found in 16-month-old VPS35D620N/+ mice. Normal function of VPS35-containing retromer is needed for activity of Wnt/β-catenin cascade, which participates in protection and survival of SNpc DAergic neurons. It was hypothesized that (D620N) VPS35 mutation causes the malfunction of VPS35 and resulting impaired activity of Wnt/β-catenin pathway. Protein levels of Wnt1 and nuclear β-catenin were reduced in SN of 16-month-old VPS35D620N/+ knockin mice. Downregulated protein expression of survivin, which is a target gene of nuclear β-catenin, and upregulated protein levels of active caspase-8 and active caspase-9 were observed in SN of VPS35D620N/+ mice at age of 16 months. VPS35 is involved in controlling morphology and function of mitochondria. Impaired function of VPS35 caused by (D620N) mutation could lead to abnormal morphology and malfunction of mitochondria. A significant decrease in mitochondrial size and resulting mitochondrial fragmentation was found in tyrosine hydroxylase-positive and neuromelanin-positive SNpc DAergic neurons of 16-month-old VPS35D620N/+ mice. Mitochondrial complex I activity or complex IV activity was reduced in SN of 16-month-old VPS35D620N/+ mice. Increased level of mitochondrial ROS and oxidative stress were found in SN of 16-month-old VPS35D620N/+ mice. Levels of cytosolic cytochrome c and active caspase-3 were increased in SN of VPS35D620N/+ mice aged 16 months. Our results suggest that PARK17 mutant (D620N) VPS35 impairs activity of Wnt/β-catenin signaling pathway and causes abnormal morphology and dysfunction of mitochondria, which could lead to neurodegeneration of SNpc DAergic cells.

show abstract

Section: Discussionmentioning

confidence: 99%

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Dysregulated Wnt signaling serves an important role in the progression of PD through brain inflammation and impaired adult neurogenesis. Depletion of canonical Wnt signaling components has demonstrated a neuroprotective effect on midbrain dopaminergic neurons in a mouse model of PD ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes and pathways in Parkinson's disease through integrated analysis

Wang¹,

Liu²,

Chen³

2017

Molecular Medicine Reports

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive, degenerative neurological disease, typically characterized by tremors and muscle rigidity. The present study aimed to identify differentially expressed genes (DEGs) between patients with PD and healthy patients, and clarify their association with additional biological processes that may regulate factors that lead to PD. An integrated analysis of publicly available Gene Expression Omnibus datasets of PD was performed. DEGs were identified between PD and normal blood samples. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses, as well as protein-protein interaction (PPI) networks were used to predict the functions of identified DEGs. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to validate the predicted expression levels of identified DEGs in whole blood samples obtained from patients with PD and normal healthy controls. A total of 292DEGs were identified between the PD and normal blood samples. Of these, 156 genes were significantly upregulated and 136 genes were significantly downregulated in PD samples following integrated analysis of four PD expression datasets. The 10 most upregulated and downregulated genes were used to construct a PPI network, where ubiquitin C-terminal hydrolase L1 (UCHL1), 3-phosphoinositide dependent protein kinase 1 (PDPK1) and protein kinase cAMP-activated catalytic subunit β (PRKACB) demonstrated the highest connectivity in the network. DEGs were significantly enriched in amoebiasis, vascular smooth muscle contraction, and the Wnt and calcium signaling pathways. The expression levels of significant DEGs, UCHL1, PDPK1 and PRKACB were validated using RT-qPCR analysis. The findings revealed that UCHL1 and PDPK1 were upregulated and PRKACB was downregulated in patients with PD when compared with normal healthy controls. In conclusion, the results indicate that the significant DEGs, including UCHL1, PDPK1 and PRKACB may be associated with the development of PD. In addition, these factors may be involved in various signaling pathways, including amoebiasis, vascular smooth muscle contraction and the Wnt and calcium signaling pathways.

show abstract

“…In this state, up-regulation of active GSK-3β results in the phosphorylation and rapid degradation of β-catenin and increases DA neuron vulnerability, degeneration, and apoptosis ( L’Episcopo et al, 2014 ). Therefore, targeting Wnt signaling could be an effective strategy for neuroprotection/repair in PD ( Parish and Arenas, 2007 ; L’Episcopo et al, 2011a , 2014 ; Arenas, 2014 ; Dai et al, 2014 ; Serafino et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Atrial Natriuretic Peptide Acts as a Neuroprotective Agent in in Vitro Models of Parkinson’s Disease via Up-regulation of the Wnt/β-Catenin Pathway

Baldeschi

Pittaluga

Andreola

et al. 2018

Front. Aging Neurosci.

View full text Add to dashboard Cite

In the last decades increasing evidence indicated a crucial role of the Wnt/β-catenin signaling in development of midbrain dopaminergic (mDA) neurons. Recently dysregulation of this pathway has been proposed as a novel pathomechanism leading to Parkinson’s disease (PD) and some of the molecules participating to the signaling have been evaluated as potential therapeutic targets for PD. Atrial natriuretic peptide (ANP) is a cardiac-derived hormone having a critical role in cardiovascular homeostasis. ANP and its receptors (NPRs) are widely expressed in mammalian central nervous system (CNS) where they could be implicated in the regulation of neural development, synaptic transmission and information processing, as well as in neuroprotection. Until now, the effects of ANP in the CNS have been mainly ascribed to the binding and activation of NPRs. We have previously demonstrated that ANP affects the Wnt/β-catenin signaling in colorectal cancer cells through a Frizzled receptor-mediated mechanism. The purpose of this study was to investigate if ANP is able to exert neuroprotective effect on two in vitro models of PD, and if this effect could be related to activation of the Wnt/β-catenin signaling. As cellular models of DA neurons, we used the proliferating or RA-differentiated human neuroblastoma cell line SH-SY5Y. In both DA neuron-like cultures, ANP is able to positively affect the Wnt/β-catenin signaling, by inducing β-catenin stabilization and nuclear translocation. Importantly, activation of the Wnt pathway by ANP exerts neuroprotective effect when these two cellular systems were subjected to neurotoxic insult (6-OHDA) for mimicking the neurodegeneration of PD. Our data support the relevance of exogenous ANP as an innovative therapeutic molecule for midbrain, and more in general for brain diseases for which aberrant Wnt signaling seems to be involved.

show abstract

Depletion of canonical Wnt signaling components has a neuroprotective effect on midbrain dopaminergic neurons in an MPTP-induced mouse model of Parkinson’s disease

Cited by 15 publications

References 34 publications

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

(D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

Identification of key genes and pathways in Parkinson's disease through integrated analysis

Atrial Natriuretic Peptide Acts as a Neuroprotective Agent in in Vitro Models of Parkinson’s Disease via Up-regulation of the Wnt/β-Catenin Pathway

Contact Info

Product

Resources

About