Lysosome functions mainly rely on their ability to either degrade substrates or release them into the extracellular space. Lysosomal storage disorders (LSDs) are commonly characterized by a chronic lysosomal accumulation of different substrates, thereby causing lysosomal dysfunctions and secretion defects. However, the early effects of substrate accumulation on lysosomal homeostasis have not been analyzed so far. Here, we describe how the acute accumulation of a single substrate determines a rapid centripetal redistribution of the lysosomes, triggering their expansion and reducing their secretion, by limiting the motility of these organelles toward the plasma membrane. Moreover, we provide evidence that such defects could be explained by a trapping mechanism exerted by the extensive contacts between the enlarged lysosomes and the highly intertwined membrane structures of the endoplasmic reticulum which might represent a crucial biological cue ultimately leading to the clinically relevant secondary defects observed in the LSD experimental models and patients.

Early onset effects of single substrate accumulation recapitulate major features of LSD in patient-derived lysosomes / Scerra, Gianluca; De Pasquale, Valeria; Pavone, Luigi Michele; Caporaso, Maria Gabriella; Mayer, Andreas; Renna, Maurizio; D'Agostino, Massimo. - In: ISCIENCE. - ISSN 2589-0042. - 24:7(2021), p. 102707. [10.1016/j.isci.2021.102707]

Early onset effects of single substrate accumulation recapitulate major features of LSD in patient-derived lysosomes

Scerra, Gianluca;De Pasquale, Valeria;Pavone, Luigi Michele;Caporaso, Maria Gabriella;Renna, Maurizio;D'Agostino, Massimo
2021

Abstract

Lysosome functions mainly rely on their ability to either degrade substrates or release them into the extracellular space. Lysosomal storage disorders (LSDs) are commonly characterized by a chronic lysosomal accumulation of different substrates, thereby causing lysosomal dysfunctions and secretion defects. However, the early effects of substrate accumulation on lysosomal homeostasis have not been analyzed so far. Here, we describe how the acute accumulation of a single substrate determines a rapid centripetal redistribution of the lysosomes, triggering their expansion and reducing their secretion, by limiting the motility of these organelles toward the plasma membrane. Moreover, we provide evidence that such defects could be explained by a trapping mechanism exerted by the extensive contacts between the enlarged lysosomes and the highly intertwined membrane structures of the endoplasmic reticulum which might represent a crucial biological cue ultimately leading to the clinically relevant secondary defects observed in the LSD experimental models and patients.
2021
Early onset effects of single substrate accumulation recapitulate major features of LSD in patient-derived lysosomes / Scerra, Gianluca; De Pasquale, Valeria; Pavone, Luigi Michele; Caporaso, Maria Gabriella; Mayer, Andreas; Renna, Maurizio; D'Agostino, Massimo. - In: ISCIENCE. - ISSN 2589-0042. - 24:7(2021), p. 102707. [10.1016/j.isci.2021.102707]
File in questo prodotto:
File Dimensione Formato  
Scerra G. et al. 2021.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Licenza: Dominio pubblico
Dimensione 5.63 MB
Formato Adobe PDF
5.63 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/854102
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 12
  • ???jsp.display-item.citation.isi??? 13
social impact