L1 neural cell adhesion molecule is a survival factor for fetal dopaminergic neurons

Cell adhesion molecules play a central role in neural development and are also critically involved in axonal regeneration and synaptic plasticity in the adult nervous system. We investigated whether the neural cell adhesion molecule L1 was capable of stimulating survival and differentiation in the mid-brain dopaminergic neurons which degenerate in Parkinson's disease. Monoclonal L1 antibodies, known to enhance neurite outgrowth, were substrate-coated or added at the time of plating to medium of cultures containing mid-brain dopaminergic neurons from 14-day-old fetal rats. Tritiated dopamine uptake per well and the number of tyrosine hydroxylase-immunopositive neurons increased in a dose-dependent manner with increasing concentrations of L1 antibody, suggesting that L1 acts directly or indirectly as a growth factor for dopaminergic neurons. A monoclonal L1 antibody not enhancing neurite outgrowth was ineffective. The growth-promoting effects of L1 antibodies on dopaminergic neurons in culture did not appear to be mediated by the cAMP-activated protein kinase A pathway, since combined treatment with a phosphodiesterase inhibitor had only additive effects on the L1-induced increase of dopamine uptake, and in addition, antibodies against L1 failed to protect cultures of dopaminergic neurons against the neurotoxin MPP+, whereas pretreatment with forskolin and phosphodiesterase type-IV inhibitors was strongly protective.