Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy

Fuenzalida, Marco; Espinoza, Claudia; Pérez, Miguel A.; Tapia-Rojas, Cheril; Cuitiño, Loreto; Brandan, Enrique; Inestrosa, Nibaldo C.

doi:10.1016/j.nbd.2015.11.018

Cited by 13 publications

(7 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, in addition to proteins with a muscle origin, likely found in the serum proteome as a consequence of sarcolemma leakage [ 31 ], our analysis pointed out several proteins involved in cell signaling that, given their biological role, it is not surprising to detect in blood serum. Our results are in line with growing evidences suggesting that the cellular structural instability caused by the lack of dystrophin affects different signaling pathways [ 32 – 34 ]. In particular, the network-based pathway enrichment analysis implemented in NASFinder identified nine pathways as significantly enriched and, among the influential nodes, different transcription factors belonging to the FoxO family were identified as possible regulators.…”

Section: Discussionsupporting

confidence: 91%

Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy

et al. 2018

View full text Add to dashboard Cite

Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome.

show abstract

Section: Discussionsupporting

confidence: 91%

Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In addition, the mdx: Smpd3 −/− mice performed significantly fewer head-dips (a marker of anxiety behavior in the hole-board test) than the mdx mice. In the CA1 region of the hippocampus of mdx mice, abnormal synaptic plasticity caused by a reduction in gamma aminobutyric acid (GABA) efficacy has been reported [14,57]. nSMase2/Smpd3 inhibition blocks TNF-alpha-induced excitatory postsynaptic currents from CA1 pyramidal cells [29].…”

Section: Discussionmentioning

confidence: 99%

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Matsuzaka

Tanihata

Ooshima

et al. 2020

BMC Med

View full text Add to dashboard Cite

Background Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. Methods To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). Results Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus. Conclusions nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.

show abstract

“…Molecular pathways, which usually encompass an amply range of biological molecules, drive the different cellular processes and, ultimately, determine the cellular fate. In this regard, the signaling pathways mediated by the Wnt ligands are involved in diverse aspects of cell-cell communication, including the regulation of cell proliferation, the occurrence of fibrosis, and cellular morphogenesis ( Cisternas et al, 2014 ; Fuenzalida et al, 2016 ; Gammons and Bienz, 2018 ). Currently, 19 Wnt ligands have been described in vertebrates, which may initiate either of two signaling pathways called the canonical and the non-canonical pathways ( Nusse and Clevers, 2017 ; Oliva et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Inestrosa

Tapia-Rojas

Lindsay

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Wnt signaling constitutes a fundamental cellular and molecular pathway, necessary from proper embryogenesis to function-maintenance of fully developed complex organisms. In this regard, Wnt pathway plays a crucial role in both the development of the central nervous system and in maintaining the structure and function of the neuronal circuits, and it has been suggested that its dysregulation is critical in the onset of several pathologies including cancer and neurodegenerative disorders, such as Alzheimer’s disease (AD). Due to its relevance in the maintenance of the neuronal activity and its involvement in the outbreak of devastating diseases, we explored the age-related changes in the expression of Wnt key components in the cortex and hippocampus of 7 to 72-months-old Octodon degus ( O. degus ), a Chilean long-living endemic rodent that has been proposed and used as a natural model for AD. We found a down-regulation in the expression of different Wnt ligands (Wnt3a, Wnt7a, and Wnt5a), as well as in the Wnt co-receptor LRP6. We also observed an increase in the activity of GSK-3β related to the down-regulation of Wnt activity, a fact that was confirmed by a decreased expression of Wnt target genes. Relevantly, an important increase was found in secreted endogenous Wnt inhibitors, including the secreted-frizzled-related protein 1 and 2 (SFRP-1 and SFRP-2) and Dickkopf-1 (Dkk-1), all them antagonists at the cell surface. Furthermore, treatment with Andrographolide, a labdane diterpene obtained from Andrographis paniculata , prevents Wnt signaling loss in aging degus . Taken together, these results suggest that during the aging process Wnt signaling activity decreases in the brain of O. degus .

show abstract

Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy

Cited by 13 publications

References 55 publications

Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy

Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy

The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Contact Info

Product

Resources

About