Abstract
BACKGROUND AND METHODS: An in vitro system of motoneurons was established from mice carrying a transgene for a human superoxide dismutase-1 (SOD-1) with a gly 93 ala mutation that has been characterized and used to compare the effects of glial cell line-derived neurotrophic factor (GDNF) on motoneurons expressing the mutant gene with those on normal motoneurons. RESULTS: Recombinant (100 ng/ml) significantly promoted the survival of a subpopulation of choline acetyltransferase (ChAT)-immunoreactive motoneurons that were also immunoreac- tive for the homeoprotein islet-1 in cul- tures from both wild type and mutant SOD-1 mice. However, GDNF did not increase the total number of ChAT-immunoreactive neurons in cultures from either wild type or transgenic mice. A distinct subpopulation of islet- 1-immunoreactive motoneurons charac- terized by a soma 3 1/2 times larger and a ten-fold increase in neurite length was observed exclusively in GDNF-treated cultures. In cultures from mutant SOD-1 mice, there were 3 1/2 times as many motoneurons of this subpopulation as in sclerosis (FALS). These cultures were wild type cultures at 6 days in vitro. In addition, this subpopulation of neurons survived for 10 days in vitro, the longest time point studied, in culture from mutant SOD-1 mice, but not in cultures from wild type mice. This subpopulation was also present at 6 days in vitro in cultures from mutant SOD-1 mice that received GDNF at 3 days in vitro instead of at the time of plating, suggesting that GDNF promotes the differentiation of these neurons. CONCLUSION: Our observations suggest that the expression of a mutant SOD-1 gene, as occurs in familial ALS, does not compromise the trophic effects of GDNF on motoneuron survival, but may affect the development of motoneurons. (ALS 2000: 1:113–122)