Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington's disease transgenic mice.
Ciliary neurotrophic factor (CNTF) has been shown to prevent behavioral deficits and striatal degeneration in neurotoxic models of Huntington's disease (HD), but its effect in a genetic model has not been evaluated. Lentiviral vectors expressing the human CNTF or LacZ reporter gene were therefore injected in the striatum of wild-type (WT) and transgenic mice expressing full-length huntingtin with 72 CAG repeats (YAC72). Behavioral analysis showed increased locomotor activity in 5- to 6-month-old YAC72-LacZ mice compared to WT-LacZ animals. Interestingly, CNTF expression reduced the activity levels of YAC72 mice compared to control animals. In both WT and YAC72 mice, CNTF expression was demonstrated in striatal punches, up to a year after lentiviral injection. Stereological analysis revealed that the number of LacZ and DARPP-32-positive neurons were decreased in YAC72-LacZ mice compared to WT-LacZ animals. Assessment of the benefit of CNTF expression in the YAC72 mice was, however, complicated by a down-regulation of DARPP-32 and to a lesser extent of NeuN in all mice treated with CNTF. The expression of the neuronal marker NADPH-d was unaffected by CNTF, but expression of the astrocytic marker glial fibrillary acidic protein (GFAP) was increased. Finally, a reduction of the number of striatal dark cells was observed in YAC mice treated with CNTF compared to LacZ. These data indicate that sustained striatal expression of CNTF can be achieved with lentiviruses. Further studies are, however, needed to investigate the intracellular signaling pathways mediating the long-term effects of CNTF expression on dopamine signaling, glial cell activation and how these changes may affect HD pathology.
Zala
Diana
D
Institute of Neuroscience, Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland.
Bensadoun
Jean-Charles
JC
Pereira de Almeida
Luis
L
Leavitt
Blair R
BR
Gutekunst
Claire-Anne
CA
Aebischer
Patrick
P
Hayden
Michael R
MR
Déglon
Nicole
N
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000473:pathology; D020934:Ciliary Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis; D013995:Time; D019076:Transgenes
D015415:Biomarkers; D020934:Ciliary Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins