Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ

Butler, David; Joshi, Shubhada N.; Genst, Erwin De; Baghel, Ankit S.; Dobson, Christopher M.; Messer, Anne

doi:10.1371/journal.pone.0165964

Cited by 54 publications

(65 citation statements)

References 49 publications

(63 reference statements)

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“…NbSyn87, which targets a central region within the C‐terminal domain (residues 118–128) of α‐syn, has also been found to destabilize the secondary and tertiary structures of the protein, and inhibit fibril formation and disrupt toxic oligomer species protein in a cell‐free system model of fibrillation . In addition, both NbSyn2 and NbSyn87 displayed neuroprotective actions in both in vitro and in vivo models of PD . Remarkably, recent surface plasmon resonance and spectroscopy findings supported that α‐syn posttranslational modifications may impinge on the binding affinity of NbSyn87.…”

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 95%

“…57 In addition, both NbSyn2 and NbSyn87 displayed neuroprotective actions in both in vitro and in vivo models of PD. 58,59 Remarkably, recent surface plasmon resonance and spectroscopy findings supported that α-syn posttranslational modifications may impinge on the binding affinity of NbSyn87. Indeed, although Ser129 phosphorylation did not substantially affect the NbSyn87/α-syn interaction, this could be significantly reduced by Tyr125 phosphorylation, 60 suggesting that in order to understand the clinical validity of intrabodies, we should know more on the features of patient-specific α-syn pathology.…”

Section: The Possible Approaches To Directly Target α-Syn Pathologymentioning

confidence: 97%

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The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

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Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 95%

Section: The Possible Approaches To Directly Target α-Syn Pathologymentioning

confidence: 97%

The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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“…Recently, VH14 and NbSyn87 intrabodies, targeting the NAC region and C-terminus of α-syn respectively, have been shown to interfere with α-syn aggregation in vitro [219,220]. VH14 and NbSyn87 combined with the PEST motif that targets the ubiquitin-proteasome system, have additionally been shown to block α-syn accumulation and attenuate proteasomal stress [221,222]. VH14*PEST proved to be more successful in targeting α-syn accumulation and showed very little neuroinflammation, demonstrating its potential for future potential therapies.…”

Section: Alternative Immunizationsmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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“…PD is associated with misfolded forms of the protein α-synuclein, which therefore has been considered of interest as a potential drug target [143]. Several α-synuclein intrabodies and engineered versions thereof have been described to reduce aggregation and toxicity in vitro [144][145][146][147][148]. In vivo, gene therapy using AAV-based vectors has been performed to deliver α-synuclein intrabodies into rats.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

et al. 2020

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To interfere with cell function, many scientists rely on methods that target DNA or RNA due to the ease with which they can be applied. Proteins are usually the final executors of function but are targeted only indirectly by these methods. Recent advances in targeted degradation of proteins based on proteolysis-targeting chimaeras (PROTACs), ubiquibodies, deGradFP (degrade Green Fluorescent Protein) and other approaches have demonstrated the potential of interfering directly at the protein level for research and therapy. Proteins can be targeted directly and very specifically by antibodies, but using antibodies inside cells has so far been considered to be challenging. However, it is possible to deliver antibodies or other proteins into the cytosol using standard laboratory equipment. Physical methods such as electroporation have been demonstrated to be efficient and validated thoroughly over time. The expression of intracellular antibodies (intrabodies) inside cells is another way to interfere with intracellular targets at the protein level. Methodological strategies to target the inside of cells with antibodies, including delivered antibodies and expressed antibodies, as well as applications in the research areas of neurobiology, viral infections and oncology, are reviewed here. Antibodies have already been used to interfere with a wide range of intracellular targets. Disease-related targets included proteins associated with neurodegenerative diseases such as Parkinson's disease (α-synuclein), Alzheimer's disease (amyloid-β) or Huntington's disease (mutant huntingtin [mHtt]). The applications of intrabodies in the context of viral infections include targeting proteins associated with HIV (e.g. HIV1-TAT, Rev, Vif, gp41, gp120, gp160) and different oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-Barr virus, and they have been used to interfere with various targets related to different processes in cancer, including oncogenic pathways, proliferation, cell cycle, apoptosis, metastasis, angiogenesis or neo-antigens (e.g. p53, human epidermal growth factor receptor-2 [HER2], signal transducer and activator of transcription 3 [STAT3], RAS-related RHO-GTPase B (RHOB), cortactin, vascular endothelial growth factor receptor 2 [VEGFR2], Ras, Bcr-Abl). Interfering at the protein level allows questions to be addressed that may remain unanswered using alternative methods. This review addresses why direct targeting of proteins allows unique insights, what is currently feasible in vitro, and how this relates to potential therapeutic applications.Therapeutic antibodies are valuable drugs, which mostly act outside of cells.Reaching the numerous drug targets that reside inside cells by antibodies is possible in vitro and allows unique insights compared with other methods.Applying antibodies inside cells for therapeutic purposes has been explored in animal models and promises specific therapeutic benefits in neurobiology, virology and oncology.

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Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ

Cited by 54 publications

References 49 publications

The good and bad of therapeutic strategies that directly target α‐synuclein

The good and bad of therapeutic strategies that directly target α‐synuclein

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology

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