A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages

• Autor(a) principal: Pereira, Mafalda M. A.
• Data de Publicação: 2017
• Outros Autores: Mahú, Inês, Seixas, Elsa, Martinéz-Sánchez, Noelia, Kubasova, Nadiya, Pirzgalska, Roksana M, Cohen, Paul, Dietrich, Marcelo O, López, Miguel, Bernardes, Gonçalo J. L., Domingos, Ana I.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.7/746
• topic: Chemical modification; Molecular neuroscience; Neuroimmunology; Peripheral nervous system

Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.