A Role for BDNF-Trkb Signaling in the Modulation of Superoxide Dismutase-1 Expression

Superoxide dismutase-1 (SOD1) has been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (fALS), a degenerative motor neuron disease more commonly known as Lou Gehrig’s disease. The mechanism by which it causes degeneration and the extent of its involvement are currently unknown, although the present consensus is that a toxic gain-of-function mutation is involved. Our lab has previously demonstrated, via a cDNA expression screen, that the TrkB receptor and the guanine nucleotide exchange factor, RasGRF-1, modulate SOD1 expression at the protein level, suggesting that cell signaling pathways associated with TrkB signaling are involved in regulating the expression of SOD1. Overexpressing these proteins for long or ‘chronic’ time periods of 24-48 hours in a motor neuron-like cell line lead to a significant decrease in SOD1 protein levels. Subsequent experiments using TrkB mutants and pharmacological inhibitors of pathways known to be associated with TrkB revealed that the kinase activity of the receptor is necessary and that partial TrkB signaling is sufficient for suppression. Conversely, treatment with brain-derived neurotrophic factor (BDNF), an activator of this pathway, over shorter or ‘acute’ time periods increased SOD1 protein levels. Further analyses using qPCR, a human SOD1 promoter Lucifersase assay, and inhibitors of the proteasome and translation machinery provide evidence that in both the acute and chronic phase, BDNF-TrkB signaling is modulating SOD1 expression at the level of translation. Taken as a whole, these data demonstrate that BDNF-TrkB signaling is involved in the regulation of SOD1 expression via translation and that the expression pattern of SOD1 is bi-phasic in response to the duration of the stimulus. These findings may have implications for therapeutic modification of mutant SOD1 levels in ALS patients.