Abstract
The pathophysiology of Amyotrophic Lateral Sclerosis (ALS), a disease caused by the gradual degeneration of motoneurons, is still largely unknown. Insufficient neurotrophic support has been cited as one of the causes of motoneuron cell death. Neurotrophic factors such as BDNF have been evaluated in ALS human clinical trials, but yielded disappointing results attributed to the poor pharmacokinetics and pharmacodynamics of BDNF. In the inherited ALS G93A SOD1 animal model, deletion of the BDNF receptor TrkB.T1 delays spinal cord motoneuron cell death and muscle weakness through an unknown cellular mechanism. Here we show that TrkB.T1 is expressed ubiquitously in the spinal cord and its deletion does not change the SOD1 mutant spinal cord inflammatory state suggesting that TrkB.T1 does not influence microglia or astrocyte activation. Although TrkB.T1 knockout in astrocytes preserves muscle strength and co-ordination at early stages of disease, its specific conditional deletion in motoneurons or astrocytes does not delay motoneuron cell death during the early stage of the disease. These data suggest that TrkB.T1 may limit the neuroprotective BDNF signaling to motoneurons via a non-cell autonomous mechanism providing new understanding into the reasons for past clinical failures and insights into the design of future clinical trials employing TrkB agonists in ALS.