title: Local GDNF expression mediated by lentiviral vector protects facial nerve motoneurons but not spinal motoneurons in SOD1(G93A) transgenic mice.
abstract: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are associated with mutations in the cytosolic Cu/Zn superoxide dismutase 1 (SOD1) gene. Transgenic SOD1 mice constitute useful models of ALS to screen therapeutical approaches. Glial cell line-derived neurotrophic factor (GDNF) holds promises for the treatment of motoneuron disease. In the present study, GDNF expression in motoneurons of SOD1(G93A) transgenic mice was assessed by facial nucleus or intraspinal injection of lentiviral vectors (LV) encoding GDNF. We show that lentiviral vectors allow the expression for at least 12 weeks of GDNF that was clearly detected in motoneurons. This robust intraspinal expression did, however, not prevent the loss of motoneurons and muscle denervation of transgenic mice. In contrast, LV-GDNF induced a significant rescue of motoneurons in the facial nucleus and prevented motoneuron atrophy. The differential effect of GDNF on facial nucleus versus spinal motoneurons suggests different vulnerability of motoneurons in ALS.
authors.affiliation: Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne, EPFL, 1015 Lausanne, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Guillot
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Anne
authors.initials: A
authors.lastname: Zurn
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000818:Animals; D001284:Atrophy; D005154:Facial Nerve / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase