Résumé
The leaner mouse carries a mutation in the gene encoding the alpha1A subunit of P/Q-type calcium channels. Leaner mice exhibit extensive cerebellar granule and Purkinje cell loss that results in cerebellar dysfunction. A previous study suggested that a small population of leaner Purkinje cells undergo apoptosis, however the cell death mode of the rest of degenerating Purkinje cells has not been identified. In order to investigate the mechanisms underlying leaner Purkinje cell death, gene arrays that contain 243 cell death related genes were carried out. To increase the chance of detecting Purkinje cell specific genes, laser capture microdissection was employed to obtain Purkinje cell enriched samples. The gene array analysis revealed several potential genes that are involved in autophagic cell death pathway including cathepsin D, a key lysosomal protease that triggers autophagic degradation. Further analysis on LC3, which is a hallmark for autophagic cell death showed that leaner Purkinje cells are degenerating via autophagic process. The present study provides evidence that calcium channel defects trigger different modes of neurodegeneration in the cerebellum.
Sujets)
Animaux , Souris , Apoptose , Autophagie , Canaux calciques , Cathepsine D , Mort cellulaire , Maladies du cervelet , Cervelet , Microdissection au laser , Cellules de PurkinjeRésumé
The leaner mouse carries a mutation in the gene encoding the alpha1A subunit of P/Q-type calcium channels. Leaner mice exhibit extensive cerebellar granule and Purkinje cell loss that results in cerebellar dysfunction. A previous study suggested that a small population of leaner Purkinje cells undergo apoptosis, however the cell death mode of the rest of degenerating Purkinje cells has not been identified. In order to investigate the mechanisms underlying leaner Purkinje cell death, gene arrays that contain 243 cell death related genes were carried out. To increase the chance of detecting Purkinje cell specific genes, laser capture microdissection was employed to obtain Purkinje cell enriched samples. The gene array analysis revealed several potential genes that are involved in autophagic cell death pathway including cathepsin D, a key lysosomal protease that triggers autophagic degradation. Further analysis on LC3, which is a hallmark for autophagic cell death showed that leaner Purkinje cells are degenerating via autophagic process. The present study provides evidence that calcium channel defects trigger different modes of neurodegeneration in the cerebellum.