Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates.
Huntington's disease (HD) is a neurological disorder characterized by striatal degeneration, motor symptoms and complex neuropsychiatric alterations. There is currently no genetic model of HD in non-human primates (NHPs). In this study we investigated neuropathological and behavioral changes following injections of lentiviral vectors encoding a fragment of mutated huntingtin (Htt171-82Q) into the dorsolateral sensorimotor putamen of macaques. In the first study, we injected Htt171-82Q into one hemisphere and a lentiviral vector encoding Htt171-19Q or saline into the other, and studied the animals for 9 weeks. During this period, when apomorphine was administered into Htt171-19Q/82Q animals, it induced progressive chorea, dystonia and ipsilateral turning behavior, whereas animals infected with Htt171-19Q/19Q showed no abnormal behavior. After 9 weeks, the putamen of animals infected with Htt171-82Q presented neuritic and nuclear Htt aggregates, reactive astrocytes and loss of the neuronal marker NeuN. In a second study, we injected Htt171-82Q bilaterally into the dorsolateral putamen. From week 15 after infection, these animals progressively developed spontaneous dyskinesia of the legs, arms, and trunk and, in one case, tics that persisted for up to 30 weeks. The present study constitutes a proof-of-principle for the development of a genetic model of HD in NHP.
Palfi
Stéphane
S
Atomic Energy Commission, Institute of Biomedical Imaging, MIRCen, Place du Général Leclerc, Orsay, France.
Brouillet
Emmanuel
E
Jarraya
Béchir
B
Bloch
Jocelyne
J
Jan
Caroline
C
Shin
Masahiro
M
Condé
Françoise
F
Li
Xiao-Jiang
XJ
Aebischer
Patrick
P
Hantraye
Philippe
P
Déglon
Nicole
N
D000818:Animals; D015415:Biomarkers; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008252:Macaca fascicularis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009068:Movement; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011699:Putamen / Q000378:metabolism*
D015415:Biomarkers; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D005973:Glutamine; D004298:Dopamine