Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.

Lysosomal positioning diseases: beyond substrate storage

Scerra, Gianluca
Co-primo
;
De Pasquale, Valeria
Co-primo
;
Scarcella, Melania;Caporaso, Maria Gabriella;Pavone, Luigi Michele
;
D'Agostino, Massimo
2022

Abstract

Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/899826
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