학술논문
Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons.
Document Type
Academic Journal
Author
Pecho-Vrieseling E; 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2].; Rieker C; 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2].; Fuchs S; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Bleckmann D; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Esposito MS; 1] Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. [2] Biozentrum, University of Basel, Basel, Switzerland.; Botta P; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Goldstein C; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Bernhard M; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Galimberti I; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Müller M; Novartis Institutes for Biomedical Research, Basel, Switzerland.; Lüthi A; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Arber S; 1] Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. [2] Biozentrum, University of Basel, Basel, Switzerland.; Bouwmeester T; Novartis Institutes for Biomedical Research, Basel, Switzerland.; van der Putten H; 1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2] National Contest for Life (NCL) Foundation against Batten Disease Hamburg, Germany.; Di Giorgio FP; Novartis Institutes for Biomedical Research, Basel, Switzerland.
Source
Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE
Subject
Language
English
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.