Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide

Kristen Ditaranto-Desimone, Mitsuo Saito, T. L. Tekirian, Mariko Saito, Martin Berg, Gene Dubowchik, Brian Soreghan, Stefani Thomas, Neville Marks, Austin J. Yang

Research output: Contribution to journalArticle

Abstract

Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer's disease. Dysregulation of the lysosomal system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an in vitro age-related pathology paradigm that models lipofuscin accumulation. Our model consists of the treatment of cultured primary mouse neurons with lysosomotropic detergents. We have observed that one of the earliest biochemical changes associated with lysosomotropic detergent-induced membrane instability is a loss of the endosomal/lysosomal proton gradient integrity, followed by an activation of sphingomyelin hydrolysis and ceramide accumulation within enlarged endosomal/lysosomal vesicles. In addition, we demonstrate that ceramide accumulation correlates with the activation of proximal procaspases-8 and -9 as well as distal caspase-3, prior to the appearance of cell death. Taken together, we propose that disturbances of the endosomal/lysosomal system, in addition to the activation of the sphingomyelinase hydrolysis cycle, play essential roles in the course of post-mitotic neuronal aging. The abnormal accumulation of undigested lipids and proteins within dysfunctional endosomal/lysosomal vesicle populations during the process of pathological aging may serve as triggers of the cell death programs that are associated with downstream neurodegeneration.

Original languageEnglish (US)
Pages (from-to)523-531
Number of pages9
JournalBrain Research Bulletin
Volume59
Issue number6
DOIs
StatePublished - Feb 15 2003

ASJC Scopus subject areas

  • Neuroscience(all)

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    Ditaranto-Desimone, K., Saito, M., Tekirian, T. L., Saito, M., Berg, M., Dubowchik, G., Soreghan, B., Thomas, S., Marks, N., & Yang, A. J. (2003). Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide. Brain Research Bulletin, 59(6), 523-531. https://doi.org/10.1016/S0361-9230(02)00948-6