Kennedy's disease: A triplet repeat disorder or a motor neuron disease?

Two definite genetic causes of adult motor neuron degeneration have been identified to date: CAG repeat expansion in the androgen receptor gene in Kennedy's disease and point mutations in the SOD1 gene, encoding the enzyme, Cu/Zn superoxide dismutase, in some familial forms of amyotrophic lateral sclerosis. Although both have unrelated genetic causes, Kennedy's disease and SOD1-linked amyotrophic lateral sclerosis share several pathogenic features. First, expanded androgen receptor and mutant Cu/Zn superoxide dismutase have a propensity to aggregate into insoluble complexes and form inclusion bodies in affected neurons. Deposits of mutant proteins could be detrimental to neuronal viability by interfering with the normal housekeeping functions of chaperones and of the ubiquitin/proteasome system. Secondly, cytoskeletal function may be impaired in both diseases as decreased transactivational activity of expanded androgen receptor may cause an abnormal pattern of tubulin expression in motor neurons in Kennedy's disease and disruption of neurofilament organisation is a hallmark of amyotrophic lateral sclerosis. The concept of activation of overlapping cell death cascades by two distinct genetic defects could help elucidating downstream pathogenic processes and may provide novel targets for pharmacological intervention or gene therapy for the treatment of motor neuron disorders. (C) 2001 Elsevier Science Inc