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.

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

“…51 The presence of abnormal mitochondria in LSDs was initially attributed to the general defect of the autophagic pathway-ineffective lysosomalautophagosomal fusion. 13,52 However, recent studies have indicated that multiple mechanisms which occur prior to the entrapment of aberrant mitochondria into autophagosomes underlie their accumulation in these disorders.…”

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…Analysis in mouse models of multiple sulphatase deficiency and mucopolysaccharidosis indicated that changes in cholesterol levels determine the ability of lysosomes to fuse with endocytic and autophagic vesicles 39 through the regulation of the SNARE fusion machinery. 21 Studies in Niemann Pick type C patient cells and in mouse models showed that cholesterol also influences autophagy initiation by enhancing Beclin1 levels 40 or SNARE-mediated autophagosome maturation.…”

A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

“…Autophagy is vital for basal homeostasis and for promoting survival during cellular stress by nutrient recycling and removal of damaged proteins and organelles 8 . Importantly, lysosomal dysfunction is tightly linked to defective protein clearance via the autophagy pathway [9][10][11] .…”

“…The clinical picture of MSD is complex and combines the symptoms of individual sulfatase deficiencies including severe neurodegeneration, skeletal abnormalities, facial dysmorphism, organomegaly and premature death 7 . Recent studies, including the generation of the Sumf1 À / À mouse, have elucidated important links between the pathogenesis of MSD and inhibition of the autophagy pathway 4,9 .…”