Details

Autor(en) / Beteiligte

• Carsana, Emma Veronica
• Lunghi, Giulia
• Prioni, Simona
• Mauri, Laura
• Loberto, Nicoletta
• Prinetti, Alessandro
• Zucca, Fabio Andrea
• Bassi, Rosaria
• Sonnino, Sandro
• Chiricozzi, Elena
• Duga, Stefano
• Straniero, Letizia
• Asselta, Rosanna
• Soldà, Giulia
• Samarani, Maura
• Aureli, Massimo

Titel

Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A

Ist Teil von

• Journal of molecular neuroscience, 2022-07, Vol.72 (7), p.1482-1499

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. In SM-loaded NPA fibroblasts, we found the blockage of the autophagy flux and the impairment of the mitochondrial compartment paralleled by the altered transcription of several genes, mainly belonging to the electron transport chain machinery and to the cholesterol biosynthesis pathway. In addition, SM loading induces the nuclear translocation of the transcription factor EB that promotes the lysosomal biogenesis and exocytosis. Interestingly, we obtained similar biochemical findings in the brain of the NPA mouse model lacking ASM (ASMKO mouse) at the neurodegenerative stage. Our work provides a new in vitro model to study NPA etiopathology and suggests the existence of a pathogenic lysosome-plasma membrane axis that with an impairment in the mitochondrial activity is responsible for the cell death.