Transgenic and gene-targeting approaches to model disorders of motor neurons

Abstract The motor neuron diseases (MND) are an etiologically heterogeneous group of disorders characterized by weakness and muscle atrophy. These clinical signs are attributable to the involvement of lower motor neurons; the presence of spasticity and hyperreflexia indicates involvement of upper motor neurons. Depending on the characteristics of the disease process, vulnerable cells develop inclusions, alterations in the cytoskeleton, etc., before undergoing cell death. Over the past several years, significant progress has been made in understanding the genetics of some of these disorders, including familial amyotrophic lateral sclerosis (FALS), spinal muscular atrophy (SMA), and spinal bulbar muscular atrophy (SBMA). For example, some of the autosomal dominant cases of FALS are linked to mutations in the superoxide dismutase 1 (SOD1) gene. Several groups have introduced these SOD1 mutations into transgenic mice, and these animals develop features of the human disease. Other investigators have used transgenic strategies to overexpress wild-type (wt) or mutant neurofilament (NF) genes, and some of these mice show abnormalities of the neuronal cytoskeleton that resemble those occurring in sporadic amyotrophic lateral sclerosis (ALS). Finally, in efforts to define trophic influences on these cells, investigators have used gene-targeting strategies to ablate genes coding for these factors or their receptors and to assess the consequences of the null state on behavior and cell phenotype. This review outlines some of the progress that has been made in modeling disorders of motor neurons, either by introducing mutant SOD1 transgenes or by overexpressing wt or mutant NF genes, and the recent advances made using gene-targeting strategies to define trophic dependencies of motor neurons.