Sergey S. Novoselov

University College London

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Michael E. Cheetham

University College London

Giampietro Schiavo

University College London

Dimitra Athanasiou

University College London

Naheed Kanuga

University College London

Sunaina Surana

University College London

Guzhova

Institute of Cytology

Linda Greensmith

University College London

Bernadett Kalmár

University College London

Margulis Ba

Institute of Cytology

Sandy Richter

University of Padua

Cooperative Institutions

University College London

National Hospital for Neurology and Neurosurgery

King's College London

Queen Mary University of London

UK Dementia Research Institute

University College Hospital

Institute of Ophthalmology

Sobell House

Moorfields Eye Hospital

Imperial College London

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[Expression of Hsp70 and Hdj1 chaperone proteins in human tumor cells].

PubMed (2004)

Sergey S. Novoselov Verbova Mv Vasil'eva Ev Vorob'ëva Nk Margulis Ba

Heat shock proteins (Hsp), or "stress proteins", play an important role in maintenance of cellular homeostasis both under normal conditions and during cellular stress. We tested malignant female urogenital and breast tumors for Hsp70 and Hdj1 (Hsp40) chaperones. Immunoenzyme procedure (based on Hsp70 and ATP interaction) was used to assay Hsp70 levels. Hsp70 and Hdj1 expression was higher in malignant cells than in benign ones. We were the first to demonstrate the feasibility of using Hdj1 expression as a novel prognostic factor for neoplastic disease.

Chaperone (clinical)

Neoplastic disease

Homeostasis

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Citations (5)

Functional analysis of the tyrosine phosphatase LAR in the endocytosis of the tetanus toxin

Toxicon (2021)

Sunaina Surana Sandy Richter Sergey S. Novoselov Giampietro Schiavo

10.1016/j.toxicon.2020.11.493

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The Molecular Chaperone BiP Maintains Rod Opsin Mobility in the Endoplasmic Reticulum

Investigative Ophthalmology & Visual Science (2012)

Dimitra Athanasiou Maria Kosmaoglou Naheed Kanuga Sergey S. Novoselov Adrienne W. Paton

Chaperone (clinical)

Opsin

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Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1^G93A mouse model of ALS

Journal of Neurochemistry (2008)

Bernadett Kalmár Sergey S. Novoselov Anna L. Gray Michael E. Cheetham Boris A. Margulis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motoneuron degeneration, resulting in muscle paralysis and death, typically within 1-5 years of diagnosis. Although the pathogenesis of ALS remains unclear, there is evidence for the involvement of proteasome dysfunction and heat shock proteins in the disease. We have previously shown that treatment with a co-inducer of the heat shock response called arimoclomol is effective in the SOD(G93A) mouse model of ALS, delaying disease progression and extending the lifespan of SOD(G93A) mice (Kieran et al. 2004). However, this previous study only examined the effects arimoclomol when treatment was initiated in pre- or early symptomatic stages of the disease. Clearly, to be of benefit to the majority of ALS patients, any therapy must be effective after symptom onset. In order to establish whether post-symptomatic treatment with arimoclomol is effective, in this study we carried out a systematic assessment of different treatment regimes in SOD(G93A) mice. Treatment with arimoclomol from early (75 days) or late (90 days) symptomatic stages significantly improved muscle function. Treatment from 75 days also significantly increased the lifespan of SOD(G93A) mice, although treatment from 90 days has no significant effect on lifespan. The mechanism of action of arimoclomol involves potentiation of the heat shock response, and treatment with arimoclomol increased Hsp70 expression. Interestingly, this up-regulation in Hsp70 was accompanied by a decrease in the number of ubiquitin-positive aggregates in the spinal cord of treated SOD(G93A) mice, suggesting that arimoclomol directly effects protein aggregation and degradation.

Pathogenesis

10.1111/j.1471-4159.2008.05595.x

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Citations (160)

NUB1 modulation of GSK3β reduces tau aggregation

Human Molecular Genetics (2012)

Emma Richet Amy M. Pooler Teresa Rodríguez-Blanco Sergey S. Novoselov Gunter Schmidtke

Abnormal phosphorylation of the microtubule-associated protein tau in neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration, is associated with disrupted axonal transport and synaptic dysfunction ultimately manifesting as histopathological lesions of protein aggregates. Glycogen synthase kinase 3β (GSK3β) may be critical for the pathological hyperphosphorylation of tau. Here, we examined the role of the proteasome-associated protein Nedd8 ultimate buster 1 (NUB1) in the neuropathogenic phosphorylation and aggregation of tau. We reveal that NUB1 interacted with both tau and GSK3β to disrupt their interaction, and abolished recruitment of GSK3β to tau inclusions. Moreover, NUB1 reduced GSK3β-mediated phosphorylation of tau and aggregation of tau in intracellular inclusions. Strikingly, NUB1 induced GSK3β degradation. Deletion of the NUB1 ubiquitin-like (UBL) domain did not impair the interaction with tau and GSK3β, and the ability to suppress the phosphorylation and aggregation of tau was not affected. However, the UBL motif was necessary for GSK3β degradation. Deletion of the NUB1 ubiquitin-associated (UBA) domain abrogated the ability of NUB1 to interact with and degrade GSK3β. Moreover, the UBA domain was required to suppress the aggregation of tau. Silencing of NUB1 in cells stabilized endogenous GSK3β and exacerbated tau phosphorylation. Thus, we propose that NUB1, by regulating GSK3β levels, modulates tau phosphorylation and aggregation, and is a key player in neurodegeneration associated with tau pathology. Moreover, NUB1 regulation of GSK3β could modulate numerous signalling pathways in which GSK3β is a centrally important effector.

Hyperphosphorylation

NEDD8

10.1093/hmg/dds376

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Citations (31)

The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex

The EMBO Journal (2024)

Sunaina Surana David Villarroel‐Campos Elena R. Rhymes Maria Kalyukina Chiara Panzi

Abstract Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear. Here, we show that the receptor-type protein tyrosine phosphatases LAR and PTPRδ interact with the nidogen-TeNT complex, enabling its neuronal uptake. Binding of LAR and PTPRδ to the toxin complex is mediated by their immunoglobulin and fibronectin III domains, which we harnessed to inhibit TeNT entry into motor neurons and protect mice from TeNT-induced paralysis. This function of LAR is independent of its role in regulating TrkB receptor activity, which augments axonal transport of TeNT. These findings reveal a multi-subunit receptor complex for TeNT and demonstrate a novel trafficking route for extracellular matrix proteins. Our study offers potential new avenues for developing therapeutics to prevent tetanus and dissecting the mechanisms controlling the targeting of physiological ligands to long-distance axonal transport in the nervous system.

Agrin

10.1038/s44318-024-00164-8

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Citations (1)

MARKERS ENDOTHELIAL DYSFUNCTION AND ANGIOGENESIS IN HYPERTENSIVE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

Journal of Hypertension (2004)

О. М. Моисеева Sergey S. Novoselov S. Villevalde E. A. Lyasnikova I. V. Emelyanov

: Tuesday, June 15, 2004: POSTER SESSIONS: Poster Session 26: Vasoactive Substances and Neurohormones

Endothelial Dysfunction

10.1097/00004872-200406002-00638

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[Dynamics of chaperone complex Hdj1-Hsp70-Bag1 as a response of erythroleukemia K562 cells to heat stress].

PubMed (2004)

Sergey S. Novoselov T. V. Novoselova Moskaleva Os Margulis Ba Guzhova

Heat shock protein Hsp70 is known to play an important role in cell protection against a variety of harmful factors. This property, at least in part, is due to Hsp70 ability to restore the native conformation of newly synthetized or damaged proteins. In this activity Hsp70 is accompanied by two proteins, Hdj1 and Bag1, that enable Hsp70 to peform cycles of binding-release of target proteins. The aim of this study was to investigate interactions of Hdj1 and Bag1 co-chaperones with Hsp70 in vivo. The accumulation of Hsp70 was stimulated by heat stress, and later, at certain periods following the stress, cell probes were collected for biochemical and microscopic analysis. The data of Western blotting showed that within 24 h after heat shock amounts of Hsp70 and Hdj1 raised to remain at the elevated level for nearly 48 h. Several time points within this period were chosen for analysis of the complexes between Hsp70 and co-chaperones. The data of reciprocal immunoprecipitation/immunoblotting and confocal microscopy showed that Hsp70-Hdj1 complexes were detected primarily at early stage after heat shock, then Hsp70 was preferably bound to Bag1. The dynamics of chaperone complex formation and changes in their intracellular localization are discussed in terms of cell reaction to stress.

Chaperone (clinical)

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Citations (3)

The tyrosine phosphatase LAR acts as a receptor of the nidogen-tetanus toxin complex

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Sunaina Surana David Villarroel‐Campos Chiara Panzi Sergey S. Novoselov Sandy Richter

Abstract Tetanus toxin is one of the most potent neurotoxins and is the causative agent of tetanus. This neurotoxin binds to the neuromuscular junction and, after internalisation into motor neurons, undergoes long-distance axonal transport and transcytosis into spinal cord inhibitory interneurons. Inside the cytoplasm of interneurons, the catalytic chain of the toxin blocks neurotransmitter release, leading to spastic paralysis. Whilst the effects of tetanus toxin intoxication have been extensively studied, the molecular composition of its receptor complex is still poorly understood. We have previously shown that the extracellular matrix proteins nidogens are essential for binding of the toxin to the neuromuscular junction. In this study, we show that the tyrosine phosphatase LAR interacts with the nidogen-tetanus toxin complex and enables its uptake into motor neurons. Binding of LAR to the toxin complex is mediated by its fibronectin III domains, which we have harnessed to inhibit tetanus toxin entry into motor neurons. Surprisingly, this function of LAR is independent of its role in regulating the neurotrophic activity of the TrkB receptor, which has previously been shown to augment the axonal transport of signalling endosomes containing tetanus neurotoxin. These findings identify a multi-subunit complex acting as a protein receptor for tetanus neurotoxin, and demonstrate a novel endocytic trafficking route for extracellular matrix proteins in neurons. Our study paves the way for dissecting the molecular mechanisms that control the recognition and uptake of physiological ligands and pathological proteins at the neuronal plasma membrane, as well as their targeting to the axonal retrograde pathway for long-distance transport within the nervous system.

Axoplasmic transport

Neurotoxin

10.1101/2023.02.03.526966

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Citations (2)

The travel diaries of tetanus and botulinum neurotoxins

Toxicon (2017)

Sunaina Surana Andrew P. Tosolini Ione Meyer Alexander D. Fellows Sergey S. Novoselov

10.1016/j.toxicon.2017.10.008

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Citations (76)