Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus.
To date, delivery of neurotrophic factors has only allowed to transiently protect axotomized facial motoneurons against cell death. In the present report, long-term protection of these neurons was evaluated by continuously expressing the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) within the facial nucleus using a lentiviral vector system. The viral vector was injected unilaterally into the facial nucleus of 4-month-old Balb/C mice. In contrast to axotomy in other adult rodents, facial nerve lesion in these animals leads to a progressive and sustained loss and/or atrophy of >50% of the motoneurons. This model thus represents an attractive model to evaluate potential protective effects of neurotrophic factors for adult-onset motoneuron diseases, such as amyotrophic lateral sclerosis. One month after unilateral lentiviral vector injection, the facial nerve was sectioned, and the animals were killed 3 months later. Viral delivery of the GDNF gene led to long-term expression and extensive diffusion of GDNF within the brainstem. In addition, axotomized motoneurons were completely protected against cell death, because 95% of the motoneurons were present as demonstrated by both Nissl staining and choline acetyltransferase immunoreactivity. Furthermore, GDNF prevented lesion-induced neuronal atrophy and maintained proximal motoneuron axons, despite the absence of target cell reinnervation. This is the first evidence that viral-mediated delivery of GDNF close to the motoneuron cell bodies of the facial nucleus of adult mice can lead to complete and long-term protection against lesion-induced cell death.
Hottinger
A F
AF
Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Azzouz
M
M
Déglon
N
N
Aebischer
P
P
Zurn
A D
AD
D000367:Age Factors; D000818:Animals; D019771:Axotomy; D002470:Cell Survival / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000032:analysis; D005154:Facial Nerve / Q000166:cytology* / Q000502:physiology; D020220:Facial Nerve Injuries / Q000503:physiopathology; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007763:Lac Operon; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009046:Motor Neurons / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016900:Neurofilament Proteins / Q000032:analysis; D018696:Neuroprotective Agents / Q000378:metabolism*; D019076:Transgenes / Q000502:physiology; D001616:beta-Galactosidase / Q000235:genetics
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; D002795:Choline O-Acetyltransferase; D001616:beta-Galactosidase