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- A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineagesPublication . Pereira, Mafalda M. A.; 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.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.