Background: It is not clear how protein degradation systems are involved in ALS pathogenesis. Results: Transgenic mice with motor neuron-specific knock-out of proteasomes, but not of autophagy showed ALS phonotypes. Conclusion: Dysfunction of proteasome may primarily contribute to the pathogenesis of ALS than that of autophagy. Significance: Modulation of proteasome function is a promising approach toward treatment of ALS.
The ubiquitin–proteasome and autophagy–lysosome pathways are the two major routes of protein and organelle clearance. The role of the proteasome pathway in mammalian muscle has not been examined in vivo. In this study, we report that the muscle-specific deletion of a crucial proteasomal gene, Rpt3 (also known as Psmc4), resulted in profound muscle growth defects and a decrease in force production in mice. Specifically, developing muscles in conditional Rpt3-knockout animals showed dysregulated proteasomal activity. The autophagy pathway was upregulated, but the process of autophagosome formation was impaired. A microscopic analysis revealed the accumulation of basophilic inclusions and disorganization of the sarcomeres in young adult mice. Our results suggest that appropriate proteasomal activity is important for muscle growth and for maintaining myofiber integrity in collaboration with autophagy pathways. The deletion of a component of the proteasome complex contributed to myofiber degeneration and weakness in muscle disorders that are characterized by the accumulation of abnormal inclusions.
SummaryAdult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle.
The authors review 30 documented cases of intracranial and orbital cavernous angiomas treated at their institution between 1965 and 1984. The diagnosis was based on computerized tomography (CT) or surgery; three patients were treated in the pre-CT era (1965 to 1976) and 27 since the advent of CT. The number of cases diagnosed preoperatively markedly increased after the introduction of CT, and 22 cases were verified histopathologically at surgery. Six cases were in children (aged 2 months to 17 years) and 24 in adults (aged 19 to 73 years). There was no significant sex difference (male:female ratio was 14:16). Nineteen lesions were intraparenchymal, five were intraventricular, three were in the middle fossa, two were intraorbital, and one originated from the tentorium. Symptoms varied according to the site of the lesion; hemorrhage occurred in 11 cases. Calcifications were seen on CT scans in all cases, but on plain skull films in only two. Angiography revealed hypovascular masses in all cases excluding those with lesions in the middle fossa; in two cases, tumor stain could be detected only with prolonged-injection angiography. Radionuclide brain scanning showed a dense hot area in eight of 19 patients. Recent experience has shown that magnetic resonance imaging clarified anatomic relationships that were obscure on CT. The overall outcome was favorable except for one patient who died in the postoperative period. The clinical results in this series are summarized and some diagnostic and therapeutic problems are discussed.
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