p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms for this neuronal cell death are not known. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the apoptosis regulating protein p53. The protein levels and localizations of p53 are abnormal in ALS. By immunoblotting, p53 is elevated in the nuclear compartment of selectively vulnerable CNS regions in individuals with ALS compared to age-matched controls. The levels of a carboxyl-terminal degradation fragment of p53 were decreased in cases of ALS. DNA binding assay demonstrated that the increased p53 in individuals with ALS had competent DNA binding activity. Immunocytochemistry revealed that in normal human CNS p53 is expressed in subsets of nonneuronal cells, but it is found only rarely in neurons; in contrast, in individuals with ALS, p53 is frequently found in motor neurons of spinal cord and motor cortex and is upregulated in astroglia. It is concluded that p53 may participate in the mechanisms for motor neuron apoptosis in ALS. Copyright 2000 Academic Press.