application) Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. Patients suffer progressive weakness from degeneration of the motor neurons. The etiology of ALS is unknown, and there is no treatment. However, the recent finding of point mutations in the Cu/Zn superoxide dismutase (SOD1) gene and diminished SOD1 activity in some patients with familial ALS suggests strongly that oxidative stress has a role in pathogenesis. Brain-derived neurotrophic factor (BDNF) acts on motor neurons and has been shown to enhance survival and regeneration of these cells in various experimental paradigms, including oxidative stress. The applicants propose to examine animal models of oxidative stress in vitro and in vivo to determine whether BDNF inhibits the effects of oxidative injury in motor neurons, and whether oxidative stress compromises motor neuron survival and function through inhibition of BDNF signaling. To test these possibilities, they will employ three strategies. First, they will measure the effects of BDNF in trkB, the BDNF receptor, transfected immortalized cell lines. BDNF effects on cell survival and cellular antioxidant defense mechanisms will be determined. They will also establish whether oxidative injury inhibits BDNF signaling through changes in the number of receptors, their activation, or in selected downstream signaling events. Second, they will immortalize motor neurons from mice transgenic for the temperature- sensitive, simian virus 40, T-antigen oncogene under the control of the promoter for the low affinity NGF receptor. Studying motor neurons in vitro is important to understanding motor neuron diseases. Finally, they will examine in vivo the effects of BDNF on motor neurons undergoing oxidative injury due to abnormal SOD1 activity. SOD1 has a critical role in mediating free radical metabolism. Oxidative injury may result from either too much or too little SOD1 activity. They will study animal models with altered SOD1 activity. Currently, they have available transgenic mice that overexpress human SOD1, and partial trisomy 16 mice that have an extra copy of the SOD1 gene. In preliminary studies they have shown that SOD1 overactivity results in motor neuron degeneration. SOD1 mutant mice with decreased SOD1 activity are under development and will also be studied. They hope to gain insight into the effects of BDNF on motor neurons undergoing oxidative stress. These studies may reveal therapeutic strategies for the treatment of ALS.
| Grimes, M L; Zhou, J; Beattie, E C et al. (1996) Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J Neurosci 16:7950-64 |
