title: Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons.
abstract: In Huntington's disease (HD), whether transneuronal spreading of mutant huntingtin (mHTT) occurs and its contribution to non-cell autonomous damage in brain networks is largely unknown. We found mHTT spreading in three different neural network models: human neurons integrated in the neural network of organotypic brain slices of HD mouse model, an ex vivo corticostriatal slice model and the corticostriatal pathway in vivo. Transneuronal propagation of mHTT was blocked by two different botulinum neurotoxins, each known for specifically inactivating a single critical component of the synaptic vesicle fusion machinery. Moreover, healthy human neurons in HD mouse model brain slices displayed non-cell autonomous changes in morphological integrity that were more pronounced when these neurons bore mHTT aggregates. Altogether, our findings suggest that transneuronal propagation of mHTT might be an important and underestimated contributor to the pathophysiology of HD.
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2].
authors.forename: Eline
authors.initials: E
authors.lastname: Pecho-Vrieseling
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2].
authors.forename: Claus
authors.initials: C
authors.lastname: Rieker
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bleckmann
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. [2] Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Esposito
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Botta
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Chris
authors.initials: C
authors.lastname: Goldstein
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Bernhard
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Galimberti
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lüthi
authors.affiliation: 1] Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. [2] Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Arber
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2] National Contest for Life (NCL) Foundation against Batten Disease Hamburg, Germany.
authors.forename: Herman
authors.initials: H
authors.lastname: van der Putten
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Di Giorgio
mesh_terms: D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells; D005260:Female; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000166:cytology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins