Heat-shock protein abducted in ALS

Abstract

A fully functional mind trapped inside a body that is becoming progressively paralysed – this is the horror of amyotrophic lateral sclerosis (ALS), a degenerative motor-neuron disease. Studies of spinal-cord tissue and cerebrospinal fluid of ALS patients suggest that increased levels of oxidative stress and accumulation of the excitatory amino-acid neurotransmitter glutamate contribute to the degeneration of the motor neurons. Some cases of autosomal dominant inherited ALS are caused by mutations in the gene encoding Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and transgenic mice expressing the mutant human gene develop progressive degeneration of spinal-cord motor neurons and paralysis, thus providing an excellent animal model of ALS. Cu/Zn-SOD is an antioxidant enzyme, but the mutations that cause ALS do not affect the function of this enzyme. Instead, they result in the gain of an adverse property of the enzyme, the nature of which remains to be established. Biochemical analyses have suggested that the ALS mutations alter the conformation of Cu/Zn-SOD such that the copper ion – normally buried deep within a pocket in the protein – becomes accessible to hydrogen peroxide, which results in the generation of the highly toxic hydroxyl radical.