Abstract
Brain Derived Neurotrophic Factor (BDNF) exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS). To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1G93A ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders.
Highlights
Neurotrophins are potent regulators of survival and function of mammalian nervous system neurons [1,2,3]
At 20 weeks, deletion of TrkB.T1 did not confer any protection to SOD1 mutant motoneurons since both SOD1;T12/2 and SOD1 animals lost about 45% motoneurons compared to WT mice (Fig. 1)
At this age we found that both motoneuron numbers and rota-rod performance are indistinguishable between SOD1 and SOD1;T12/2 mice, SOD1 transgenic mice predominantly scored in the 3–4 range, a reflection of severe impairments in locomotor activity due to muscle weakness and paralysis, while deletion of TrkB.T1 in these animals improved the score to the 2–3 neurological range
Summary
Neurotrophins are potent regulators of survival and function of mammalian nervous system neurons [1,2,3] These functions are mediated by their binding to the Trk tyrosine kinase receptors and p75, a member of the tumor necrosis factor receptor family. The TrkB and TrkC loci, in addition to the full-length kinase receptors, can generate, by alternative splicing, truncated receptors lacking the canonical intracellular tyrosine kinase domain [reviewed in [6]] How these receptor isoforms coordinate cellular or systemic neurotrophin responses is still poorly understood. Truncated receptors appear to affect neuronal viability only when over-expressed in artificial or pathological situations [11,12,13] They are the most highly expressed isoforms in the adult mammalian brain [14,15,16]. Phosphorylation of the TrkB receptor is reduced suggesting that TrkB signaling impairments in ALS are not caused by insufficient neurotrophin supply but rather by a mechanism affecting the TrkB response to BDNF [18,19]
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