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Lysosomal storage diseases as disorders of autophagy

Carmine Settembre, Alessandro Fraldi, David C. Rubinsztein and Andrea Ballabio

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The cellular turnover of proteins and organelles requires cooperation between the autophagic and the lysosomal degradation pathways. A crucial step in this process is the fusion of the autophagosome with the lysosome. In our study we demonstrate that in Lysosomal Storage Disorders (LSDs) accumulation of undegraded substrates in lysosomes, due to deficiency of specific lysosomal enzymes, impairs the fusion between autophagosomes and lysosomes. This, in turn, leads to a progressive accumulation of poly-ubiquitinated protein aggregates and of dysfunctional mitochondria. These findings suggest that neurodegeneration in LSDs may share some mechanisms with late-onset neurodegenerative disorders in which the accumulation of protein aggregates is a prominent feature.

Authors

Carmine Settembre

Telethon Institute of Genetics and Medicine (TIGEM)

Alessandro Fraldi

Telethon Institute of Genetics and Medicine (TIGEM)

David C. Rubinsztein

Cambridge Institute for Medical Research

Andrea Ballabio

Telethon Institute of Genetics and Medicine (TIGEM)

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.