Complete and Long-Term Rescue of Lesioned Adult Motoneurons by Lentiviral-Mediated Expression of Glial Cell Line-Derived Neurotrophic Factor in the Facial Nucleus

• Published in: The Journal of neuroscience Vol. 20; no. 15; pp. 5587 - 5593
• Main Authors: Hottinger, Andreas F, Azzouz, Mimoun, Deglon, Nicole, Aebischer, Patrick, Zurn, Anne D
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.08.2000; Society for Neuroscience
• Subjects: Age Factors; Animals; Axotomy; beta-Galactosidase - genetics; Cell Survival - genetics; Choline O-Acetyltransferase - analysis; Facial Nerve - cytology; Facial Nerve - physiology; Facial Nerve Injuries - physiopathology; Gene Expression Regulation, Viral; Genetic Therapy; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Lac Operon; Lentivirus; Lentivirus - genetics; Mice; Mice, Inbred BALB C; Motor Neurons - chemistry; Motor Neurons - cytology; Motor Neurons - enzymology; Nerve Growth Factors; Nerve Tissue Proteins - genetics; Neurofilament Proteins - analysis; Neuroprotective Agents - metabolism; Transgenes - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-15-05587.2000

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.