The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

Yang, Chen; Yan, Qi; Sun, Zhitang

doi:10.3389/fmolb.2021.711710

Cited by 55 publications

(35 citation statements)

References 56 publications

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“…TBIs result in a wide breadth of pathologies, with excitotoxicity contributing to many TBI-induced sequelae [ 43 ]. Previously, Shh signaling was reported to reduce excitotoxicity following middle cerebral artery occlusion in rodents [ 45 , 46 ], though it was never examined following TBI in adult zebrafish. To test if Shh signaling could affect glutamate-induced excitotoxicity, undamaged fish were either left untreated, treated with the Smo agonist purmorphamine, which is a Shh signaling activator, or treated with both purmorphamine and cyclopamine.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the results of Shh signaling activators have been inconsistent. For example, in epileptic rodents, Feng et al [ 70 ] reported that increased Shh expression exacerbated seizure activity and negatively regulated extracellular glutamate, while others reported data suggesting that Shh activity upregulated EAAT2 expression, reduced astrocyte reactivity, and combated excitotoxicity [ 45 , 46 , 71 , 72 ]. Other studies reported that Shh activation is neuroprotective [ 23 , 37 , 38 , 39 ] and is effective in regenerative therapies [ 35 , 73 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

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Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

et al. 2021

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Approximately 2 million individuals experience a traumatic brain injury (TBI) every year in the United States. Secondary injury begins within minutes after TBI, with alterations in cellular function and chemical signaling that contribute to excitotoxicity. Post-traumatic seizures (PTS) are experienced in an increasing number of TBI individuals that also display resistance to traditional anti-seizure medications (ASMs). Sonic hedgehog (Shh) is a signaling pathway that is upregulated following central nervous system damage in zebrafish and aids injury-induced regeneration. Using a modified Marmarou weight drop on adult zebrafish, we examined PTS following TBI and Shh modulation. We found that inhibiting Shh signaling by cyclopamine significantly increased PTS in TBI fish, prolonged the timeframe PTS was observed, and decreased survival across all TBI severities. Shh-inhibited TBI fish failed to respond to traditional ASMs, but were attenuated when treated with CNQX, which blocks ionotropic glutamate receptors. We found that the Smoothened agonist, purmorphamine, increased Eaat2a expression in undamaged brains compared to untreated controls, and purmorphamine treatment reduced glutamate excitotoxicity following TBI. Similarly, purmorphamine reduced PTS, edema, and cognitive deficits in TBI fish, while these pathologies were increased and/or prolonged in cyclopamine-treated TBI fish. However, the increased severity of TBI phenotypes with cyclopamine was reduced by cotreating fish with ceftriaxone, which induces Eaat2a expression. Collectively, these data suggest that Shh signaling induces Eaat2a expression and plays a role in regulating TBI-induced glutamate excitotoxicity and TBI sequelae.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

et al. 2021

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“…Hedgehog signaling pathway: The Sonic hedgehog (SHH) signaling pathway is involved in neurogenesis, neural patterning and cell survival during nervous system development [ 66 , 67 ]. SHH signaling requires intact primary cilia in brain cells and fails with structurally disrupted cilia.…”

Section: Discussionmentioning

confidence: 99%

Artificial Intelligence and Circulating Cell-Free DNA Methylation Profiling: Mechanism and Detection of Alzheimer’s Disease

Bahado‐Singh

Radhakrishna

Gordevičius³

et al. 2022

Cells

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Background: Despite extensive efforts, significant gaps remain in our understanding of Alzheimer’s disease (AD) pathophysiology. Novel approaches using circulating cell-free DNA (cfDNA) have the potential to revolutionize our understanding of neurodegenerative disorders. Methods: We performed DNA methylation profiling of cfDNA from AD patients and compared them to cognitively normal controls. Six Artificial Intelligence (AI) platforms were utilized for the diagnosis of AD while enrichment analysis was used to elucidate the pathogenesis of AD. Results: A total of 3684 CpGs were significantly (adj. p-value < 0.05) differentially methylated in AD versus controls. All six AI algorithms achieved high predictive accuracy (AUC = 0.949–0.998) in an independent test group. As an example, Deep Learning (DL) achieved an AUC (95% CI) = 0.99 (0.95–1.0), with 94.5% sensitivity and specificity. Conclusion: We describe numerous epigenetically altered genes which were previously reported to be differentially expressed in the brain of AD sufferers. Genes identified by AI to be the best predictors of AD were either known to be expressed in the brain or have been previously linked to AD. We highlight enrichment in the Calcium signaling pathway, Glutamatergic synapse, Hedgehog signaling pathway, Axon guidance and Olfactory transduction in AD sufferers. To the best of our knowledge, this is the first reported genome-wide DNA methylation study using cfDNA to detect AD.

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“…A potential role of such an established developmental pathway in age-related neurodegeneration is emerging. Dysregulation of the Shh pathway has been reported in neurodegenerative diseases such as Alzheimer's disease 47,58,59 , Parkinson's disease 60,61 , Huntington's disease 62 and ALS [63][64][65] , demonstrating the importance of fully functioning Shh pathway, not only during development, but also during ageing. While further research is needed, we provide evidence that this dysfunction of this overlooked organelle is a contributing factor to the complex pathobiology in ALS.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the key pathway components localize within the organelle or have been otherwise associated with the ciliary function [42][43][44] . Shh signaling is involved in multiple developmental and several adult homeostatic processes [45][46][47] . Consequently, precise regulation is required via controlled intraflagellar transport (IFT) of positive (SMO) or negative (GPR161; SUFU) regulators inside or out of the cilium 38,39,43,44,48,49 .…”

Section: Shh Signaling Is Perturbed Upon C21orf2 Knockdownmentioning

confidence: 99%

C21orf2 mutations found in ALS disrupt primary cilia function

Decker

Zelina

Moens

et al. 2022

Preprint

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SUMMARYAmyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects 1 in 400 people. Almost 40 genes have been associated with ALS, currently explaining about 15% of the ALS risk. These genes tend to cluster in certain disease pathways such as protein quality control, RNA metabolism and axonal function. Despite these advances, adequate treatments for ALS patients are still missing. In this study, we investigate the role of a newly discovered ALS gene, C21orf2, in ALS pathology. We show that C21orf2 is localized to the basal body of the primary cilium and plays an important role in ciliogenesis in vitro and in vivo. Knock down of C21orf2 also lowers cilia frequency and length in human iPSC-derived spinal motor neurons (sMNs). Furthermore, we show that intraflagellar transport is impaired, causing primary cilia to fail in transducing extracellular signals essential in the sonic hedgehog pathway. ALS-associated mutations in C21orf2 lead to loss of binding to centrosomal proteins, loss of proper localization at the basal body and hereby prevent C21orf2 from carrying out its normal function in cilia by loss-of-function. Finally, we confirm that sMNs derived from iPSCs from ALS patients with C21orf2 mutations display similar cilia dysfunction and have disturbed sonic hedgehog signaling. Collectively, our data reveal impaired cilia homeostasis as a novel disease mechanism at play in ALS, opening new avenues for further research.

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The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

Cited by 55 publications

References 56 publications

Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

Prophylactic Activation of Shh Signaling Attenuates TBI-Induced Seizures in Zebrafish by Modulating Glutamate Excitotoxicity through Eaat2a

Artificial Intelligence and Circulating Cell-Free DNA Methylation Profiling: Mechanism and Detection of Alzheimer’s Disease

C21orf2 mutations found in ALS disrupt primary cilia function

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