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Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates

Authors
  • Maxan, Alexander
  • Sciacca, Giacomo
  • Alpaugh, Melanie
  • Tao, Zhu
  • Breger, Ludivine
  • Dehay, Benjamin
  • Ling, Zhang
  • Qin, Chuan
  • Cisbani, Giulia
  • Masnata, Maria
  • Salem, Shireen
  • Lacroix, Steve
  • Oueslati, Abid
  • Bezard, Erwan
  • Cicchetti, Francesca
Publication Date
May 01, 2020
Identifiers
DOI: 10.1016/j.nbd.2020.104951
PMID: 32439599
OAI: oai:HAL:inserm-02615641v1
Source
HAL-INRIA
Keywords
Language
English
License
Unknown
External links

Abstract

In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent protein (GFP) or GFP coupled to HTT-Exon1 (19Q or 103Q) to the central nervous system of adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing and post-mortem analyses to determine the long-term consequences of AAV injection. Both mice and non-human primates demonstrated behavioral changes at 2-3 weeks post-surgery. In mice, these changes were absent after 3 months while in non-human primates, they persisted in the majority of tested animals. Post-mortem analysis revealed that spreading of the aggregates was limited, although the virus did spread between synaptically-connected brain regions. Despite the small degree of spreading, the presence of mHTT generated changes in endogenous huntingtin (HTT) levels in both models. Together, these results suggest that viral expression of mHTTExon1 can induce spreading and seeding of HTT in both mice and non-human primates.

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