Molecular mechanism and gene therapy of familial ALS

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Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting predominantly motor neurons in the central nervous system. There has been no effective treatment, and the duration is usually 2-5 years. About 5-10% of ALS is thought to be familial (FALS) with an autosomal dominant inheritance, or less often recessive.We report here seven FALS families associated with four different missense mutations of the Cu/Zn SOD gene (D6F, H46R, L84V, A90V, I104F, S134N, and V148I), and each family has unique clinical characteristics. Protein tyrosin nitration of spinal motor neurons was found in ALS patients, but not in control subjects. With transgenic mice of G93A Cu/Zn SOD gene mutation, we found early and selective impairment of fast axonal transport by ligation of sciatic nerves. Furthermore, immunoreactivity of cell survival signal such as Akt and PI3K showed early decrease in spinal motor neurons, but immunoreactivities for cell death signals such as caspases or TUNEL was not positive until the advance stage of motor neuron death, indicating a critical imbalance of cell survival and death signals in dying motor neurons. In addition, -mediated Lace gene was effectively transferred and expressed in muscles and spinal motor neurons in transgenic symptomatic mice, and established a therapic basis for human ALS patients.