P75 Involved in the Ubiquitination of α-synuclein in Rotenone-based Parkinson’s Disease Models

Chen, Yan; Hou, Yiwei; Yang, Jiaolong; Du, Ruofei; Chen, Chao; Chen, Fang; Wang, Hongcai; Ge, Ruli; Chen, Jinbo

doi:10.1016/j.neuroscience.2018.07.048

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…Our NGF-mediated apoptotic effect was also associated with p65NFkB nuclear translocation. NFkB transcription factor is composed of p50/p65 subunits close to cytoplasmic IkB inhibitors to prevent nuclear translocation, a route observed in several cell types in the presence of the pan-neurotrophin p75 NTR receptor activation 30,31 . Our finding on NGF-mediated p65-NFkB nuclear translocation in these myoFBs strongly suggest the ability of NGF to increase myoFB apoptosis while in unresponsive myoFBs it might modulate the release of some proinflammatory as well as pro-angiogenic factors, through a p75 NTR mediated signal 11 .…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature

Esposito

Balzamino

Stigliano

et al. 2021

Sci Rep

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We previously described the profibrogenic effect of NGF on conjunctival Fibroblasts (FBs) and its ability to trigger apoptosis in TGFβ1-induced myofibroblasts (myoFBs). Herein, cell apoptosis/signalling, cytokines’ signature in conditioned media and inflammatory as well as angiogenic pathway were investigated. Experimental myoFBs were exposed to NGF (0.1–100 ng/mL), at defined time-point for confocal and biomolecular analysis. Cells were analysed for apoptotic and cell signalling activation in cell extracts and for some inflammatory and proinflammatory/angiogenic factors’ activations. NGF triggered cJun overexpression and phospho-p65-NFkB nuclear translocation. A decreased Bcl2:Bax ratio and a significant expression of smad7 were confirmed in early AnnexinV-positive myoFBs. A specific protein signature characterised the conditioned media: a dose dependent decrease occurred for IL8, IL6 while a selective increase was observed for VEGF and cyr61 (protein/mRNA). TIMP1 levels were unaffected. Herein, NGF modulation of smad7, the specific IL8 and IL6 as well as VEGF and cyr61 modulation deserve more attention as opening to alternative approaches to counteract fibrosis.

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Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature

Esposito

Balzamino

Stigliano

et al. 2021

Sci Rep

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“…Acetylation of Transcription factor EB (TFEB) facilitates its nuclear translocation and lysosome biogenesis, independent of TFEB dephosphorylation, and treatment with TSA, an inhibitor of HDACs, upregulates the expression of lysosomal genes, enhances Aβ aggregate clearance in APP/PS1 mouse brains, and improves their memory, highlighting the potential of HDAC inhibition to promote lysosome biogenesis and serve as a therapeutic strategy for neurodegenerative diseases [ 116 ]. Aberrant expression of p75 in a rotenone-based stereotactic infusion in vivo model of PD led to significant upregulation of siAH compared to the control group, and in cellular models of rotenone-mediated neurotoxicity, p75 was found to interact with siAH through immunoprecipitation, promoting nuclear expression of NF-jB (p65) that may interact with the promoter of the siAH gene, while siRNA-mediated p75 depletion reduced the upregulation of a-syn and nuclear expression of p65, and protected against rotenone-induced cell apoptosis, suggesting that p75 modulates the increased expression of a-syn, which is associated with siAH-mediated ubiquitination and nuclear expression of p65 [ 117 ]. The CDK5-GP78 pathway plays a role in the pathogenesis of PD and may be a potential drug target for its treatment, as demonstrated by the protective effects of overexpressing GP78 or interfering with GP78 Ser516 phosphorylation against MPP+-induced cell death in neurons [ 118 ].…”

Section: Treatment Strategy Based On Pptmsmentioning

confidence: 99%

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

Li,

Wang

et al. 2024

Cell Biosci

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Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein’s structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer’s disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson’s disease. Other neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.

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“…Another study demonstrated significant increase in p75NTR up‐regulation following kainic acid insult in the substantia nigra of rat model, suggesting that p75NTR may function importantly in neuronal cell survival or excitotoxic degeneration of dopamine neurons in the substantia nigra in the pathogenesis and development of PD in human beings (Wang et al, 2008). In addition, it is found that p75 depletion depressed the up‐regulation of α‐synuclein protein and nuclear expression of p65 and protected against rotenone‐induced cell apoptosis, which might be attributed to ubiquitin ligase absentia homolog (siAH)‐mediated ubiquitination and nuclear expression of p65 (Chen et al, 2018) (Table 2). The current therapeutics including drug treatment as the main means could only alleviate symptoms to a certain extent instead of effectively preventing the progression of PD, in spite of significant elevation in the quality of life of patients.…”

Section: The Regulatory Potentials Of P75ntr In Neurological Diseasesmentioning

confidence: 99%

P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases

Xiong

Chen

Deng

et al. 2022

Eur J of Neuroscience

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The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation‐induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in‐depth investigations on p75NTR‐based drug development are required to shed light on effective treatment of numerous neurological disorders.

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P75 Involved in the Ubiquitination of α-synuclein in Rotenone-based Parkinson’s Disease Models

Cited by 9 publications

References 21 publications

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature

Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

P75 neurotrophin receptor as a therapeutic target for drug development to treat neurological diseases

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