Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis.

摘要: Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of amyotrophic lateral sclerosis (fALS). The present study demonstrated impaired proteasomal function lumbar spinal cord transgenic mice expressing human SOD-1 with ALS-causing mutation G93A (SOD-1G93A) compared to non-transgenic littermates (LM) and SOD-1WT mice. Chymotrypsin-like activity was decreased as early 45 days age. By 75 days, chymotrypsin-, trypsin-, caspase-like activities proteasome were impaired, at about 50% control cord, but unchanged thoracic liver. Both total specific reduced similar extent, indicating that change function, rather than decrease levels, had occurred. Similar decreases observed NIH 3T3 cell lines fALS mutants SOD-1G93A SOD-1G41S, not controls. Although overall levels maintained mice, level 20S substantially motor neurons relative surrounding neuropil. It is concluded impairment an event contributes ALS pathogenesis.