Inhibiting cellular uptake of mutant huntingtin using a monoclonal antibody: Implications for the treatment of Huntington's disease
| Autor: | Halyna Pankevych, Stefan Bartl, Amber L. Southwell, Michela Parth, Theresa Friedrich, Alexander Maxan, Michael R. Hayden, Francesca Cicchetti, Guenther Staffler, Andreas Mairhofer, Alberto Siddu, Nina Salhat, Abid Oueslati, Katja Balazs, Markus Burkert, Oskar W. Smrzka, Linda Suzanne David |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Huntingtin medicine.drug_class Cell Mutant Monoclonal antibody Protein Aggregation Pathological lcsh:RC321-571 Therapeutic antibody 03 medical and health sciences 0302 clinical medicine medicine Huntingtin Protein Extracellular mutHTT Animals Humans Secretion lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Mice Inbred BALB C biology Chemistry Cell-to-cell propagation Antibodies Monoclonal Huntington's disease Biological Transport 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure HEK293 Cells Huntington Disease Neurology Cell culture Mutation biology.protein Female Antibody 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Neurobiology of Disease, Vol 141, Iss, Pp 104943-(2020) |
| ISSN: | 1095-953X |
| Popis: | Huntington's disease (HD) is caused by a highly polymorphic CAG trinucleotide expansion in the gene encoding for the huntingtin protein (HTT). The resulting mutant huntingtin protein (mutHTT) is ubiquitously expressed but also exhibits the ability to propagate from cell-to-cell to disseminate pathology; a property which may serve as a new therapeutic focus. Accordingly, we set out to develop a monoclonal antibody (mAB) targeting a particularly exposed region close to the aa586 caspase-6 cleavage site of the HTT protein. This monoclonal antibody, designated C6-17, effectively binds mutHTT and is able to deplete the protein from cell culture supernatants. Using cell-based assays, we demonstrate that extracellular secretion of mutHTT into cell culture media and its subsequent uptake in recipient HeLa cells can be almost entirely blocked by mAB C6-17. Immunohistochemical stainings of post-mortem HD brain tissue confirmed the specificity of mAB C6-17 to human mutHTT aggregates. These findings demonstrate that mAB C6-17 not only successfully engages with its target, mutHTT, but also inhibits cell uptake suggesting that this antibody could interfere with the pathological processes of mutHTT spreading in vivo. |
| Databáze: | OpenAIRE |
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