Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

Wang, S.-Y.; Ren, Ming; Jiang, Haiyang; Wang, J.; Yin, Xiang; Qi, Yinkuang; Wang, X.-D.; Dong, Guangtao; Wang, T.-H.; Yang, Yee‐Hong; Feng, Honglin

doi:10.1016/j.neuroscience.2015.06.002

Cited by 28 publications

(18 citation statements)

References 54 publications

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“…Therefore, we believe that there is a need for better-designed preclinical studies to present the potential beneficial effects of lithium for ALS. Our recent research showed that lithium and VPA inhibited the activation of the Notch pathway in mtSOD1 (G93A) mice [34]. However, the effects of lithium and VPA on Homer1b/c expression were unknown.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Jiang

Wang

Yin

et al. 2016

IJMS

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Background: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. Results: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. Conclusion: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Jiang

Wang

Yin

et al. 2016

IJMS

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“…Notch1 , Jag1 , Hey1 , Hes1 , and Maml1 RNA and protein were all found to be upregulated in SOD1 G93A ALS model mice; lithium and valproic acid (VPA), drugs used to treat bipolar disorder and purported to have neuroprotective properties in vivo and in vitro, reduced this upregulation in both the mouse model and human patients (Wang et al, ). Furthermore, blocking Notch signaling using a GSI or Notch1 siRNA in SOD1 G93A cells caused an upregulation of Bcl‐2 as well as downregulation of Bax and cytochrome C , consistent with a reduction in pro‐apoptotic signaling (Wang et al, ). NICD protein levels decreased in motor neurons and increased in astroglia in SOD1 G93A mice after the onset of ALS symptoms (Ma, Drannik, Jiang, Peterson, & Turnbull, ).…”

Section: Notch In Progressive Neurodegenerative Diseasesmentioning

confidence: 99%

The Notch pathway in CNS homeostasis and neurodegeneration

Artavanis‐Tsakonas

Louvi

2019

WIREs Developmental Biology

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The role of the Notch signaling pathway in neural development has been well established over many years. More recent studies, however, have demonstrated that Notch continues to be expressed and active throughout adulthood in many areas of the central nervous system. Notch signals have been implicated in adult neurogenesis, memory formation, and synaptic plasticity in the adult organism, as well as linked to acute brain trauma and chronic neurodegenerative conditions. NOTCH3 mutations are responsible for the most common form of hereditary stroke, the progressive disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Notch has also been associated with several progressive neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Although numerous studies link Notch activity with CNS homeostasis and neurodegenerative diseases, the data thus far are primarily correlative, rather than functional. Nevertheless, the evidence for Notch pathway activity in specific neural cellular contexts is strong, and certainly intriguing, and points to the possibility that the pathway carries therapeutic promise. This article is categorized under: Nervous System Development > Flies Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: General Principles

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“…Accordingly, the neuronal defensive system must be evoked to protect neurons from death (Novoselov et al, 2013; Wang et al, 2015). Identification and investigation of ALS-relevant molecular alterations may aid in the identification of potential therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells

Chen

et al. 2017

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of upper and lower motor neurons. MicroRNAs (miRNAs) are reported to be closely related to the development of ALS. However, the precise functions of miRNAs in the pathogenesis of ALS remain largely unknown. In previous studies, we determined that miRNA-193b-3p was significantly downregulated in patients with sporadic ALS (sALS). Here, we observed that miRNA-193b-3p was downregulated in the SOD1G93A mouse model of ALS and promoted cell death in NSC-34 cells. We further found that miR-193b-3p directly targeted tuberous sclerosis 1 (TSC1) to regulate mechanistic target of rapamycin complex 1 (mTORC1) activity. Downregulation of miR-193b-3p led to TSC1 increase accompanied with mTORC1 inactivation, and vice versa. Moreover, downregulation of miR-193b-3p promoted protective autophagy and cell survival in NSC-34 cells. In contrast, upregulation of miR-193b-3p activated mTORC1 signaling, leading to inhibition of autophagy and promotion of cell death. Taken together, our study suggests that downregulation of miR-193b-3p is required for cell survival by targeting TSC1/mTOR signaling in NSC-34 cells and provides a novel target for improving the clinical therapy of ALS.

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Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

Cited by 28 publications

References 54 publications

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

The Notch pathway in CNS homeostasis and neurodegeneration

Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells

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