Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus.

Abstract

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.

• Authors: A F Hottinger, M Azzouz, N Déglon, P Aebischer, A D Zurn
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 20 Issue 15 Pg. 5587-93 (Aug 01 2000) ISSN: 0270-6474 [Print] United States
• PMID: 10908595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gdnf protein, mouse
• Glial Cell Line-Derived Neurotrophic Factor
• Nerve Growth Factors
• Nerve Tissue Proteins
• Neurofilament Proteins
• Neuroprotective Agents
• Choline O-Acetyltransferase
• beta-Galactosidase

Topics

• Age Factors
• Animals
• Axotomy
• Cell Survival (genetics)
• Choline O-Acetyltransferase (analysis)
• Facial Nerve (cytology, physiology)
• Facial Nerve Injuries (physiopathology)
• Gene Expression Regulation, Viral
• Genetic 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)