Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates
Neurobiology of Disease. 2020-05-01; : 104951
DOI: 10.1016/j.nbd.2020.104951
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Maxan A(1), Sciacca G(1), Alpaugh M(1), Tao Z(2), Breger L(3), Dehay B(3), Ling
Z(2), Qin C(2), Cisbani G(4), Masnata M(1), Salem S(1), Lacroix S(5), Oueslati
A(5), Bezard E(6), Cicchetti F(7).
Author information:
(1)Centre de Recherche du CHU de Québec – Université Laval, Axe Neurosciences,
Québec, QC G1V 4G2, Canada.
(2)Institute of Laboratory Animal Sciences, China Academy of Medical Sciences,
Beijing, China.
(3)Université de Bordeaux, Institut des maladies neurodégénératives, UMR 5293,
CNRS UMR 5293, Bordeaux, France; Centre National de la Recherche Scientifique,
Institut des maladies neurodégénératives, UMR 5293, 33076 Bordeaux, France.
(4)University of Toronto, Department of Nutritional Sciences, Toronto, ON M5S
1A8, Canada.
(5)Centre de Recherche du CHU de Québec – Université Laval, Axe Neurosciences,
Québec, QC G1V 4G2, Canada; Département de Médicine Moléculaire, Université
Laval, Québec, QC G1K 0A6, Canada.
(6)Institute of Laboratory Animal Sciences, China Academy of Medical Sciences,
Beijing, China; Université de Bordeaux, Institut des maladies neurodégénératives,
UMR 5293, CNRS UMR 5293, Bordeaux, France; Centre National de la Recherche
Scientifique, Institut des maladies neurodégénératives, UMR 5293, 33076 Bordeaux,
France.
(7)Centre de Recherche du CHU de Québec – Université Laval, Axe Neurosciences,
Québec, QC G1V 4G2, Canada; Département de Psychiatrie & Neurosciences,
Université Laval, Québec, QC G1K 0A6, Canada. Electronic address:
.
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.