Age-Dependent Changes in Mitochondrial Regulatory Mechanisms in the Spinal Cord of SOD1-G93A-Transgenic Mice with the Phenotype of Amyotrophic Lateral Sclerosis.

Age-dependent changes in the expression level of genes encoding proteins responsible for mitochondrial homeostasis were studied in relation to ultrastructural abnormalities in the mitochondria of motor neurons in the anterior horns of the spinal cord in a transgenic model of amyotrophic lateral sclerosis (SOD1-G93A mice). The expression of the Drp1, Mfn2, Ppargc1a, and Nefl genes was reduced, and the expression of the Nfe2l2, Pink1, and Parkin genes was enhanced in mice with the genotype of the familial form of the disease at the age of 22 weeks corresponding to the symptomatic stage in comparison with wild-type mice (C57BL6 × SJL) and non-transgenic littermates (SOD1-G93A(Tg-)) of the same age. Comparative analysis of spinal cord tissue samples from 8 and 12 weeks-old animals revealed no significant differences in the expression levels of genes encoding proteins responsible for mitochondrial dynamics, biogenesis, and mitophagy. Electron microscopic examination showed pronounced structural alterations in mitochondria in the soma of lower motor neurons of SOD1-G93A(Tg+) mice at the symptomatic stage, which manifested in the appearance of "ring-like" mitochondrial structures, matrix swelling, destruction of membranes in the cristae, and increased number of autophagolysosomes. The role of mitochondrial homeostasis disorders in the progression of amyotrophic lateral sclerosis is discussed.