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.
Keywords: Age Factors ; Animals ; Axotomy ; Cell Survival/genetics ; Choline O-Acetyltransferase/analysis ; Facial Nerve/ cytology/physiology ; Facial Nerve Injuries/physiopathology ; Gene Expression Regulation ; Viral ; Gene Therapy ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor ; Lac Operon ; Lentivirus/ genetics ; Mice ; Mice ; Inbred BALB C ; Motor Neurons/chemistry/ cytology/enzymology ; Nerve Growth Factors ; Nerve Tissue Proteins/ genetics ; Neurofilament Proteins/analysis ; Neuroprotective Agents/ metabolism ; Transgenes/physiology ; beta-Galactosidase/genetics
Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Record created on 2007-03-09, modified on 2016-08-08