deletion of the bdnf truncated receptor trkb.t1 delays disease onset in a mouse model of amyotrophic lateral sclerosis删除脑源性神经营养因子受体trkb截短。.pdfVIP

Deletion of the BDNF Truncated Receptor TrkB.T1 Delays Disease Onset in a Mouse Model of Amyotrophic Lateral Sclerosis Sudhirkumar U. Yanpallewar, Colleen A. Barrick, Hannah Buckley, Jodi Becker, Lino Tessarollo* Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America 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 li