Development of therapies in polyglutamine diseases using hepatocyte growth factor (HGF)

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Spinal and bulbar muscular atrophy(SBMA) is an inherited motor neuron disease. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine(polyQ) tract, in the androgen receptor(Alt) gene. We generated transgenic mouse model expressing the full-length human AR containing either 24 or 97 CAG repeats under the control of a cytomegalovirus enhancer and a chicken β-actin promoter(AR-97Q mice). Hepatocyte growth factor(HGF) was initially identified and molecularly cloned as a potent mitogen for mature hepatocytes. Subsequent studies revealed that HGF exerts multiple biological effects, including mitogenic, motogenic, morphogenic, and anti-apoptotic activities in a wide variety of cells, including neurons, by binding to the c-Met receptor tyrosine kinase(c-Met). HGF is one of the most potent in vitro and in vivo survival-promoting factors for neurons. For example, neurotrophic effects of HGF have been demonstrated in cultured hippocampal neurons and in cultured embryonic spinal motoneurons, and its anti-apoptotic activity in motoneurons is comparable to that of glial cell line-derived neurotrophic factor(GDNF). In the present study, the effects of HGF on motor dysfunction were examined using double transgenic mice overexpressing mutated human AR and HGF. We cross-bred AR-97Q mice with mice over-expressing the HGF. The double transgenic mice showed improvement of their motor function, body weight, lifespan. Overexpression of HDF also ameliorated motor function in the castrated male AR-97Q mice. These findings suggest that HGF over-expression ameliorates SBMA phenotypes in mice.