Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/ mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage.

Defective autophagy, mitochondrial clearance and lipophagy in niemann-pick type B lymphocytes / Canonico B.; Cesarini E.; Salucci S.; Luchetti F.; Falcieri E.; Sario G.D.; Palma F.; Papa S.. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 11:10(2016), pp. e0165780.e0165780-e0165780.e0165810. [10.1371/journal.pone.0165780]

Defective autophagy, mitochondrial clearance and lipophagy in niemann-pick type B lymphocytes

Salucci S.;
2016

Abstract

Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/ mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage.
2016
Defective autophagy, mitochondrial clearance and lipophagy in niemann-pick type B lymphocytes / Canonico B.; Cesarini E.; Salucci S.; Luchetti F.; Falcieri E.; Sario G.D.; Palma F.; Papa S.. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 11:10(2016), pp. e0165780.e0165780-e0165780.e0165810. [10.1371/journal.pone.0165780]
Canonico B.; Cesarini E.; Salucci S.; Luchetti F.; Falcieri E.; Sario G.D.; Palma F.; Papa S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/850988
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