Cytoplasmic, lysosomal and matrix protease activities in spinal cord tissue from amyotrophic lateral sclerosis (ALS) and control patients.

The histological identification of ubiquitin-conjugated protein deposits in spinal motor neurones of patients with amyotrophic lateral sclerosis (ALS) has suggested that an underlying abnormality of intracellular protein metabolism may be responsible for the pathogenesis of the disease. In an attempt to identify such an abnormality at the biochemical level, we have undertaken a systematic investigation of a representative range of proteolytic enzyme types comprising the two major pathways (cytoplasmic and lysosomal) of intracellular protein degradation, in spinal cord tissue from ALS and control cases. No evidence of a generalised alteration in protein catabolizing proteolytic enzymes in spinal cord tissue from ALS cases was found. Only proline endopeptidase and pyroglutamyl aminopeptidase (both cytoplasmic proteases) showed significantly altered activity (increased by 76% and 119%, respectively) in ALS cases compared to normal controls. In addition to their generalised role in intracellular protein degradation, these two enzymes are involved in the processing of thyrotrophin-releasing hormone (TRH) in CNS tissues. The selective increase in activity of proline endopeptidase and pyroglutamyl aminopeptidase in ALS may represent an adaptation to maintain excitatory drive to surviving motor neurons by increased processing of TRH to its active metabolite.