Premium
Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis
Author(s) -
Kabashi Edor,
Agar Jeffrey N.,
Taylor David M.,
Minotti Sandra,
Durham Heather D.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02453.x
Subject(s) - amyotrophic lateral sclerosis , proteasome , spinal cord , lumbar spinal cord , genetically modified mouse , superoxide dismutase , endocrinology , biology , medicine , transgene , oxidative stress , neuroscience , microbiology and biotechnology , biochemistry , gene , disease
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 in the lumbar spinal cord of transgenic mice expressing human SOD‐1 with the ALS‐causing mutation G93A (SOD‐1 G93A ) compared to non‐transgenic littermates (LM) and SOD‐1 WT transgenic mice. Chymotrypsin‐like activity was decreased as early as 45 days of age. By 75 days, chymotrypsin‐, trypsin‐, and caspase‐like activities of the proteasome were impaired, at about 50% of control activity in lumbar spinal cord, but unchanged in thoracic spinal cord and liver. Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD‐1 G93A and SOD‐1 G41S , but not in SOD‐1 WT controls. Although overall levels of proteasome were maintained in spinal cord of SOD‐1 G93A transgenic mice, the level of 20S proteasome was substantially reduced in lumbar spinal motor neurons relative to the surrounding neuropil. It is concluded that impairment of the proteasome is an early event and contributes to ALS pathogenesis.