Regulatory region genetic variation is associated with FYN expression in Alzheimer's disease

Zahratka, Jeffrey A.; Shao, Yvonne; Shaw, McKenzie; Todd, Kaitlin; Formica, Shane; Khrestian, Maria; Montine, Thomas J.; Leverenz, James B.; Bekris, Lynn M.

doi:10.1016/j.neurobiolaging.2016.11.001

Cited by 6 publications

(5 citation statements)

References 60 publications

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“…For example, Fyn protein levels are increased in the brain tissue of AD patients, especially in the cerebellum and hippocampus (Zahratka et al, 2017), and the upregulation of Fyn increases the phosphorylation of tau protein on tyrosine-18 and promotes AD progression (Lee et al, 2004), whereas the inhibition of Fyn kinase activity can result in the improvement of synaptic function and memory in mice (Nygaard et al, 2014;Kaufman et al, 2015). In addition, there could exist an interaction between Aβ and Fyn.…”

Section: Discussionmentioning

confidence: 99%

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Yao

Xia

Fang

et al. 2020

Front. Aging Neurosci.

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Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. In this study, we investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice.Methods: We generated miR-369 knockout 3xTg-AD mice and investigated their cognitive behaviors by maze tests. Real-time qPCR, western blot, and immunohistochemistry were performed to evaluate the expression of the miR-369 gene, phosphorylation of tau protein, and activation of Fyn and SRPK2. Luciferase reporter assays were applied to confirm the predicted targets of miR-369.Results: Knocking out miR-369 in 3xTg AD mice aggravated cognitive impairment, promoted hyperphosphorylation of tau, and upregulated Fyn and SRPK2. Restoring miR-369 reversed the hyperphosphorylation of tau and downregulated Fyn and SRPK2. Additionally, miR-369 was shown to target the 3 UTRs of Fyn and SRPK2 to regulate their expression levels.Conclusion: Loss of miR-369 promotes tau phosphorylation by targeting the Fyn and SRPK2 signaling pathways in AD mice, and supplementation with miR-369 might be a valuable option for AD therapeutic studies.

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Section: Discussionmentioning

confidence: 99%

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Yao

Xia

Fang

et al. 2020

Front. Aging Neurosci.

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“…40,41 Besides, Xie et al proved that upregulation of FYN is associated with breast cancer development and cell proliferation, migration, and invasion through 40,41 Besides, Xie et al proved that upregulation of FYN is associated with breast cancer development and cell proliferation, migration, and invasion through …”

Section: Discussionmentioning

confidence: 99%

“…FYN (FYN proto-oncogene) is a well-known protooncogene, which has the highest abundance in brain and is closely associated with Alzheimer disease development. 40,41 Besides, Xie et al proved that upregulation of FYN is associated with breast cancer development and cell proliferation, migration, and invasion through upregulating epithelial-mesenchymal transition-related transcription factors. 42 Consistent with Xie's study, FYN is significantly upregulated in osteosarcoma samples compared with normal control (Supporting Information Table S1), and upregulation of FYN is significantly associated with shorter osteosarcoma OS ( Figure 3C) in our study.…”

Section: Discussionmentioning

confidence: 99%

“…FYN (FYN proto‐oncogene) is a well‐known proto‐oncogene, which has the highest abundance in brain and is closely associated with Alzheimer disease development . Besides, Xie et al proved that upregulation of FYN is associated with breast cancer development and cell proliferation, migration, and invasion through upregulating epithelial‐mesenchymal transition–related transcription factors .…”

Section: Discussionmentioning

confidence: 99%

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Long noncoding RNA MEG3 play an important role in osteosarcoma development through sponging microRNAs

Jiang

Zhou

et al. 2018

J of Cellular Biochemistry

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More and more evidence indicate long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) to indirectly regulate messenger RNAs (mRNAs) by acting as microRNA (miRNA) sponges, which represents a novel layer of gene regulation that plays a critical role in the development of cancers. However, functional roles and regulatory mechanisms of lncRNA‐mediated ceRNAs network in osteosarcoma are still largely unknown. Here, we comprehensively compared the expression profiles of mRNAs, lncRNAs, and miRNAs between osteosarcoma and normal samples from the Gene Expression Omnibus (GEO) to elaborate related latent mechanisms. Two lncRNAs, ie, LINC01560 and MEG3, were identified to be aberrantly expressed. Importantly, MEG3 was considered as a promising diagnostic biomarker and therapeutic target for patients with osteosarcoma according to the Kaplan‐Meier analysis of another independent osteosarcoma data set from the Cancer Genome Atlas (P = 0.05). Eventually, we successfully established a dysregulated lncRNA‐related ceRNA network, including one osteosarcoma‐specific lncRNA, three miRNAs and four mRNAs. In conclusion, this study should be beneficial for improving our understanding of the lncRNA‐mediated ceRNA regulatory mechanisms in the pathogenesis of osteosarcoma and providing it with novel candidate diagnostic and therapeutic biomarkers.

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“…Similar to preclinical studies, Pyk2 decouples from the PrPC protein complex in human AD brain (45). Changes in total and activated Fyn in post-mortem human AD brain are less clear, with conflicting results from several recent studies (46, 57, 58), but the accumulated data thus far strongly support targeting Fyn in AD whether reducing Fyn overactivation directly, or modifying pathologic Fyn-mediated changes in downstream substrates, such as Pyk2.…”

Section: Fyn and The Aβ-prpc Signaling Pathwaymentioning

confidence: 99%

Targeting Fyn Kinase in Alzheimer’s Disease

Nygaard

2018

Biological Psychiatry

130

115

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The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.

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Regulatory region genetic variation is associated with FYN expression in Alzheimer's disease

Cited by 6 publications

References 60 publications

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Long noncoding RNA MEG3 play an important role in osteosarcoma development through sponging microRNAs

Targeting Fyn Kinase in Alzheimer’s Disease

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