Abstract
Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Substitution
-
Animals
-
Axons / metabolism
-
Axons / pathology
-
Denervation
-
Disease Progression
-
Ganglion Cysts / metabolism
-
Ganglion Cysts / pathology
-
Gene Deletion
-
Inclusion Bodies / metabolism
-
Inflammation / complications
-
Inflammation / pathology
-
Inflammation / physiopathology
-
Integrases / metabolism
-
Interneurons / metabolism
-
Interneurons / pathology
-
Longevity
-
Mice
-
Mice, Knockout
-
Motor Activity
-
Motor Neuron Disease / complications
-
Motor Neuron Disease / enzymology*
-
Motor Neuron Disease / pathology*
-
Motor Neuron Disease / physiopathology
-
Motor Neurons / metabolism*
-
Motor Neurons / pathology*
-
Mutation / genetics*
-
Neuromuscular Junction / metabolism
-
Neuromuscular Junction / pathology
-
Receptor, trkB / metabolism*
-
Recombination, Genetic / genetics
-
Spinal Cord / metabolism
-
Spinal Cord / pathology
-
Superoxide Dismutase / genetics*
-
Superoxide Dismutase-1
-
Ubiquitin / metabolism
-
Ubiquitination
-
Vesicular Acetylcholine Transport Proteins / metabolism
Substances
-
Slc18a3 protein, mouse
-
Ubiquitin
-
Vesicular Acetylcholine Transport Proteins
-
Sod1 protein, mouse
-
Superoxide Dismutase
-
Superoxide Dismutase-1
-
Receptor, trkB
-
Cre recombinase
-
Integrases