The identification of a novel isoform of EphA4 and ITS expression in SOD1 G93A mice

Zhao, Jing; Boyd, Andrew W.; Bartlett, Perry F.

doi:10.1016/j.neuroscience.2017.01.038

Cited by 13 publications

(9 citation statements)

References 35 publications

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“…While it is not consistent with the potential clinical application in most case, it may be practical in familial ALS patients diagnosed with SOD1 mutation. Moreover, the early mutEphA4-Fc treatment is consistent with the report that EphA4 is likely to be more critical in early disease pathogenesis 58 . Therefore, earlier mutEphA4-Fc treatment is most likely to obtain a better clinical outcome for ALS patients.…”

Section: Discussionsupporting

confidence: 89%

Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model

Zhao

Cooper

Boyd

et al. 2018

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is an untreatable, progressive, neurodegenerative disease specifically affecting motor neurons. Recently, the tyrosine kinase receptor EphA4 was directly implicated in ALS disease progression. We report that a long-lived mutated form of the EphA4 antagonist EphA4-Fc (mutEphA4-Fc), which blocks EphA4 binding to its ligands and inhibits its function, significantly improved functional performance in SOD1G93A ALS model mice, as assessed by rotarod and hind-limb grip strength tests. Further, heterozygous motor neuron-specific EphA4 gene deletion in SOD1G93A mice promoted significant improvement in functional performance during the disease course and a delay in disease onset relative to control mice. Importantly, mice in the heterozygous deletion group showed significantly improved survival of motor neurons and architecture of endplates of neuromuscular junctions compared with control and homozygous EphA4-deletion groups. Our novel results show that EphA4 signalling directly regulates motor neuron survival and that mutEphA4-Fc is a promising therapeutic candidate to slow disease progression in ALS.

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Section: Discussionsupporting

confidence: 89%

Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model

Zhao

Cooper

Boyd

et al. 2018

Sci Rep

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“…Strikingly, almost all the Eph receptor genes yield at least one isoform that does not have kinase activity due to partial or complete truncation of the intracellular domains from alternative splicing. In addition to the roles in cancer, these Eph isoforms possess a wide array of functions in neuronal development [69,70], cell reprogramming [71] and cell adhesion and repulsion [72].…”

Section: The Non-catalytic Functions Of Alternative Eph Receptor Isofmentioning

confidence: 99%

Eph receptor signalling: from catalytic to non-catalytic functions

et al. 2019

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Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that drive Eph receptor signalling, and investigates the contribution of intra-and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. Throughout this review, we carefully analyse and reconcile the existing/conflicting data in the field, to allow researchers to further the current understanding of Eph receptor signalling. Eph receptors and ephrin ligands: an overview Receptor tyrosine kinases (RTKs) are a major type of membrane receptors, which govern cell proliferation, differentiation and mobility [1]. Deregulation of RTK signalling pathways leads to many diseases, such as cancers and developmental disorders [2]. The erythropoietin-producing hepatoma (Eph) receptor subfamily is the largest amongst the RTKs with 14 members classified into type A and type B. Compared with other RTKs, Eph receptors share

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“…Moreover, EphA receptors seems to be key player in the pathophysiology of AD and other neuropathologies, such as motor neuron degeneration in amyotrophic lateral sclerosis (ALS) [ 198 , 199 ]. It was shown in AD brains, that hippocampal distribution of EphA4 was co-localized with neuritic plaques already at early stages (Braak stage II), which suggests that EphA4 may contribute to synaptic dysfunction [ 200 ].…”

Section: Cellular Receptors Related To Aβos Activitymentioning

confidence: 99%

Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease

Mroczko

Groblewska

Litman‐Zawadzka

et al. 2018

IJMS

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It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients’ brain composed of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aβ and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AβOs) aggregation in the pathogenesis of AD. Moreover, binding of AβOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AβO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aβ oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AβO receptors related to toxic activity of oligomers.

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The identification of a novel isoform of EphA4 and ITS expression in SOD1 G93A mice

Cited by 13 publications

References 35 publications

Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model

Decreased signalling of EphA4 improves functional performance and motor neuron survival in the SOD1G93A ALS mouse model

Eph receptor signalling: from catalytic to non-catalytic functions

Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease

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