Alzheimer's Disease and Prion Protein

Zhou, Jiayi; Liu, Bingqian

doi:10.5582/irdr.2013.v2.2.35

Cited by 19 publications

(17 citation statements)

References 129 publications

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“…Interestingly, a fragment of RanBPM is found overexpressed in Alzheimer’s Disease (AD) patients and its overexpression promotes Amyloid beta (Aβ) generation and hallmarks of AD 41–45 . As PrP C propagates the neurotoxic signaling effects of Aβ 46–48 , this could implicate a mechanism whereby the effects observed by RanBPM overexpression in AD are, at least partially, a result of increased ubiquitination and proteasomal degradation of muskelin, leading to a defect in PrP C lysosomal degradation. It will be of interest to assess adult mouse models of other CTLH complex members, especially in the context of neurodegenerative diseases, to determine if there is an interplay between the CTLH complex and muskelin ubiquitination that contributes to disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

Maitland

Onea

Chiasson

et al. 2019

Sci Rep

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The multi-subunit C-terminal to LisH (CTLH) complex is the mammalian homologue of the yeast Gid E3 ubiquitin ligase complex. In this study, we investigated the human CTLH complex and characterized its E3 ligase activity. We confirm that the complex immunoprecipitated from human cells comprises RanBPM, ARMC8 α/β, muskelin, WDR26, GID4 and the RING domain proteins RMND5A and MAEA. We find that loss of expression of individual subunits compromises the stability of other complex members and that MAEA and RMND5A protein levels are interdependent. Using in vitro ubiquitination assays, we demonstrate that the CTLH complex has E3 ligase activity which is dependent on RMND5A and MAEA. We report that the complex can pair with UBE2D1, UBE2D2 and UBE2D3 E2 enzymes and that recombinant RMND5A mediates K48 and K63 poly-ubiquitin chains. Finally, we show a proteasome-dependent increase in the protein levels of CTLH complex member muskelin in RMND5A KO cells. Furthermore, muskelin ubiquitination is dependent on RMND5A, suggesting that it may be a target of the complex. Overall, we further the characterization of the CTLH complex as an E3 ubiquitin ligase complex in human cells and reveal a potential autoregulation mechanism.

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Section: Discussionmentioning

confidence: 99%

The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

Maitland

Onea

Chiasson

et al. 2019

Sci Rep

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“…At the molecular level, AD is a multifactorial disease [5]. Though the amyloid β (Aβ) protein is commonly placed in the center of AD aetiology, the scientific community has been conducting research to link Aβ with many other molecular players and processes known to contribute to disease development and progression, including the cellular prion protein (PrP C ) [6], tau hyperphosphorylation [7], oxidative stress, neuroinflammation [8], and insulin resistance [9], among others. Natural products, including flavonoids and their C -glucosyl derivatives, have been widely studied and found to interfere with one or more of these features [10].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

et al. 2019

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With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.

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“…However, within the AD context PrP c has been demonstrated to contribute to Ab pathology. PrP c serves as a high-affinity receptor for Ab oligomers [90] and upon binding this toxic species, the protein mediates toxic signal transduction cascades via Fyn Kinase [91] the results of which include the induction of tau hyperphosphorylation as well as excitotoxicity and culminates in dendritic spine loss and neuronal death [92]. PrP c has also been shown to be essential for Ab induced loss of long-term potentiation and impaired synaptic plasticity and recent reports have revealed that PrP c mediates the internalization of Ab oligomers into cells [93] as well as transcytosis across the blood--brain barrier (BBB) [94].…”

Section: The Role Of Prp C In Admentioning

confidence: 99%

Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s disease

Jovanović

Chetty

Khumalo

et al. 2015

Expert Opinion on Therapeutic Patents

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Molecular tools directed against LRP/LR, such as antibodies and small interfering RNA, could prove to be effective in the prevention of metastasis and angiogenesis while inducing apoptosis in cancers. Moreover, these strategies could also be applied to AD where LRP/LR is seen to facilitate the production and internalization of the neurotoxic Aβ peptide. This review provides a comprehensive overview of the mechanisms by which LRP/LR is involved in eliciting pathogenic events, while showing how the use of patented approaches targeting this receptor could be used to treat them.

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Alzheimer's Disease and Prion Protein

Cited by 19 publications

References 129 publications

The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s disease

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