Genetics of familial and sporadic amyotrophic lateral sclerosis

Abstract

Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) form a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of all cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. The research projects presented here aim to investigate the role of different cell types and tissues in the pathology of SOD1-linked ALS, and to identify new genetic factors involved in sporadic ALS cases. LoxP transgenic mice expressing mutated G85R SOD1, allowing transgene expression in cell and tissue specific manner, have been successfully generated. However, mice, up to 2.5 years of age, did not develop any motor neuron deficits or any developmental abnormalities. We concluded that this might be due to insufficient level of the transgene expression in our transgenic animals. Also, a number of candidate genes for ALS have been identified, such as ALS2, VEGF, PRPH, CHGA and CHGB, based on their pattern of expression and biological function. These genes have been screened for mutations in a cohort of ALS patients and, we have identified one basepair deletion in the ALS2 and in the PRPH genes, and we have also found a strong genetic association between the CHGA and CHGB genes with ALS. An in-vitro cell transfection approach has been used to investigate the biological effects of mutations within the PRPH genes and, of particular interest, this technique has revealed the first functional variants in a neurofilament associated gene ever describe in ALS