Common themes in PrP signaling: the Src remains the same

Ochs, Katharina; Málaga-Trillo, Edward

doi:10.3389/fcell.2014.00063

Cited by 11 publications

(11 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S4B). This discrepancy is likely attributed to the conformational state of affecting oAb and the type of PrP c coreceptor, but further delineations are certainly needed (43,44). In addition, the prolonged activation of LYN may potentiate oAb 1-42 -triggered neurotoxicity combined with enhanced expression of FcgRIIb, considering that the expression and phosphorylation of FcgRIIb2 are induced by oAb for .24 h in neuronal cells (45).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

View full text Add to dashboard Cite

SRC‐family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid β (Aβ)‐triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown of LYN expression inhibited Aβ1–42‐induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aβ1–42 and phosphorylated FcγRIIb2 at Tyr273 within immunoreceptor tyrosine‐based inhibitory motif in neuronal cells. With the use of the structure‐based drug design, we isolated KICG2576, an ATP‐competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half‐maximal inhibitory concentration value of 0.15 µM. KICG2576 inhibited Aβ‐ or FcγRIIb2‐induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aβ, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5‐trisphosphate 5‐phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aβ1–42‐FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aβ‐induced memory impairment. These results suggest that LYN plays a crucial role in Aβ1–42‐mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.—Gwon, Y., Kim, S.‐H., Kim, H. T., Kam, T.‐I., Park, J., Lim, B., Cha, H., Chang, H.‐J., Hong, Y. R., Jung, Y.‐K. Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN. FASEB J. 33, 4300–4313 (2019). http://www.fasebj.org

show abstract

Section: Discussionmentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

View full text Add to dashboard Cite

show abstract

“…However, ablation of Fyn function has ameliorated AD phenotype . The suggested pathological signaling cascade via SFKs is summarized in Figure , where the extracellular binding domain of Aβo activates the gatekeeper PrPC and Fyn plays a crucial role in this cascade …”

Section: Future Directions For Alzheimer's Disease Treatmentmentioning

confidence: 99%

“…159 The suggested pathological signaling cascade via SFKs is summarized in Figure 12, where the extracellular binding domain of Aβo activates the gatekeeper PrPC and Fyn plays a crucial role in this cascade. 160 Moreover, Fyn has been uniquely linked to the two major pathological hallmarks of AD, because it is not only activating by Aβ via PrPC, but also it interacts with tau. 155 It has been reported that Fyn is involved in Tau phosphorylation, which results in synapse damage, behavioral deficits and electroencephalographic deformities in APP transgenic mice.…”

Section: Fyn Kinase Inhibitionmentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

226

175

View full text Add to dashboard Cite

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

show abstract

“…Uncovering mechanisms of PrP function in vivo remains a challenging task because no overt phenotypes are evident in PrP knockout mice, save for subtle abnormalities in olfactory physiology, neurogenesis, peripheral myelination and muscle regeneration [ 9 – 13 ]. Unfortunately, the biochemical basis of these defects and their connection to prion disease are yet to be established.…”

Section: Introductionmentioning

confidence: 99%

Activation of zebrafish Src family kinases by the prion protein is an amyloid-β-sensitive signal that prevents the endocytosis and degradation of E-cadherin/β-catenin complexes in vivo

Sempou

Biasini

Pinzon-Olejua

et al. 2016

Mol Neurodegeneration

View full text Add to dashboard Cite

BackgroundPrions and amyloid-β (Aβ) oligomers trigger neurodegeneration by hijacking a poorly understood cellular signal mediated by the prion protein (PrP) at the plasma membrane. In early zebrafish embryos, PrP-1-dependent signals control cell-cell adhesion via a tyrosine phosphorylation-dependent mechanism.ResultsHere we report that the Src family kinases (SFKs) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin/β-catenin adhesion complexes in vivo. Accordingly, knockdown of PrP-1 or Fyn/Yes cause similar zebrafish gastrulation phenotypes, whereas Fyn/Yes expression rescues the PrP-1 knockdown phenotype. We also show that zebrafish and mouse PrPs positively regulate the activity of Src kinases and that these have an unexpected positive effect on E-cadherin-mediated cell adhesion. Interestingly, while PrP knockdown impairs β-catenin adhesive function, PrP overexpression enhances it, thereby antagonizing its nuclear, wnt-related signaling activity and disturbing embryonic dorsoventral specification. The ability of mouse PrP to influence these events in zebrafish embryos requires its neuroprotective, polybasic N-terminus but not its neurotoxicity-associated central region. Remarkably, human Aβ oligomers up-regulate the PrP-1/SFK/E-cadherin/β-catenin pathway in zebrafish embryonic cells, mimicking a PrP gain-of-function scenario.ConclusionsOur gain- and loss-of-function experiments in zebrafish suggest that PrP and SFKs enhance the cell surface stability of embryonic adherens junctions via the same complex mechanism through which they over-activate neuroreceptors that trigger synaptic damage. The profound impact of this pathway on early zebrafish development makes these embryos an ideal model to study the cellular and molecular events affected by neurotoxic PrP mutations and ligands in vivo. In particular, our finding that human Aβ oligomers activate the zebrafish PrP/SFK/E-cadherin pathway opens the possibility of using fish embryos to rapidly screen for novel therapeutic targets and compounds against prion- and Alzheimer's-related neurodegeneration. Altogether, our data illustrate PrP-dependent signals relevant to embryonic development, neuronal physiology and neurological disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0076-5) contains supplementary material, which is available to authorized users.

show abstract

Common themes in PrP signaling: the Src remains the same

Cited by 11 publications

References 87 publications

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Activation of zebrafish Src family kinases by the prion protein is an amyloid-β-sensitive signal that prevents the endocytosis and degradation of E-cadherin/β-catenin complexes in vivo

Contact Info

Product

Resources

About