A block of autophagy in lysosomal storage disorders

Carmine Settembre, Alessandro Fraldi, Luca Jahreiss, Carmine Spampanato, Consuelo Venturi, Diego Medina, Raquel de Pablo, Carlo Tacchetti, David C. Rubinsztein, Andrea Ballabio

Research output: Contribution to journalArticle

329 Citations (Scopus)

Abstract

Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.

Original languageEnglish
Pages (from-to)119-129
Number of pages11
JournalHuman Molecular Genetics
Volume17
Issue number1
DOIs
Publication statusPublished - Jan 1 2008

Fingerprint

Autophagy
Lysosomes
Multiple Sulfatase Deficiency Disease
Cell Death
Mucopolysaccharidosis III
alpha-Synuclein
Hydrolases
Neurodegenerative Diseases
Mitochondria
Enzymes
Proteins
Autophagosomes
Protein Aggregates

ASJC Scopus subject areas

  • Genetics

Cite this

Settembre, C., Fraldi, A., Jahreiss, L., Spampanato, C., Venturi, C., Medina, D., ... Ballabio, A. (2008). A block of autophagy in lysosomal storage disorders. Human Molecular Genetics, 17(1), 119-129. https://doi.org/10.1093/hmg/ddm289

A block of autophagy in lysosomal storage disorders. / Settembre, Carmine; Fraldi, Alessandro; Jahreiss, Luca; Spampanato, Carmine; Venturi, Consuelo; Medina, Diego; de Pablo, Raquel; Tacchetti, Carlo; Rubinsztein, David C.; Ballabio, Andrea.

In: Human Molecular Genetics, Vol. 17, No. 1, 01.01.2008, p. 119-129.

Research output: Contribution to journalArticle

Settembre, C, Fraldi, A, Jahreiss, L, Spampanato, C, Venturi, C, Medina, D, de Pablo, R, Tacchetti, C, Rubinsztein, DC & Ballabio, A 2008, 'A block of autophagy in lysosomal storage disorders', Human Molecular Genetics, vol. 17, no. 1, pp. 119-129. https://doi.org/10.1093/hmg/ddm289
Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, Medina D et al. A block of autophagy in lysosomal storage disorders. Human Molecular Genetics. 2008 Jan 1;17(1):119-129. https://doi.org/10.1093/hmg/ddm289
Settembre, Carmine ; Fraldi, Alessandro ; Jahreiss, Luca ; Spampanato, Carmine ; Venturi, Consuelo ; Medina, Diego ; de Pablo, Raquel ; Tacchetti, Carlo ; Rubinsztein, David C. ; Ballabio, Andrea. / A block of autophagy in lysosomal storage disorders. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 1. pp. 119-129.
@article{c2651d8a052b4da090045c6224ebf837,
title = "A block of autophagy in lysosomal storage disorders",
abstract = "Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.",
author = "Carmine Settembre and Alessandro Fraldi and Luca Jahreiss and Carmine Spampanato and Consuelo Venturi and Diego Medina and {de Pablo}, Raquel and Carlo Tacchetti and Rubinsztein, {David C.} and Andrea Ballabio",
year = "2008",
month = "1",
day = "1",
doi = "10.1093/hmg/ddm289",
language = "English",
volume = "17",
pages = "119--129",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - A block of autophagy in lysosomal storage disorders

AU - Settembre, Carmine

AU - Fraldi, Alessandro

AU - Jahreiss, Luca

AU - Spampanato, Carmine

AU - Venturi, Consuelo

AU - Medina, Diego

AU - de Pablo, Raquel

AU - Tacchetti, Carlo

AU - Rubinsztein, David C.

AU - Ballabio, Andrea

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.

AB - Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.

UR - http://www.scopus.com/inward/record.url?scp=37549066697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37549066697&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddm289

DO - 10.1093/hmg/ddm289

M3 - Article

C2 - 17913701

AN - SCOPUS:37549066697

VL - 17

SP - 119

EP - 129

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 1

ER -