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- Title
Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons.
- Authors
Kumar, Meenakshi Sundaram; Fowler-Magaw, Megan E.; Kulick, Daniel; Boopathy, Sivakumar; Gadd, Del Hayden; Rotunno, Melissa; Douthwright, Catherine; Golebiowski, Diane; Yusuf, Issa; Xu, Zuoshang; Brown Jr., Robert H.; Sena-Esteves, Miguel; O'Neil, Alison L.; Bosco, Daryl A.
- Abstract
ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.
- Subjects
IMMUNOGLOBULINS; AMYOTROPHIC lateral sclerosis; NEURONS; GENE silencing; PROTEINS; MOTOR neurons
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 24, p16013
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232416013