AnatomiSjukdomarKemikalier och läkemedel
Multipel sulfatasbristSulfataserCerebrosidsulfatasSfingolipidoserKondro-4-sulfatasLysosomala upplagringssjukdomarLeukodystrofi, metakromatiskDiazometanMannosidasbristsjukdomarSteryl-sulfatasArylsulfataserKarbamolylfosfatsyntas I-bristsjukdomImmunbristsyndromIktyos, X-bundenMukopolysackaridos IIKondroitinsulfataserFibroblasterMukopolysackaridos IVFiskfjällshudPyruvatkarboxylasbristsjukomIduronatsulfatas

A block of autophagy in lysosomal storage disorders. (1/9)

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.  (+info)

Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. (2/9)

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SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. (3/9)

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Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. (4/9)

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Transcriptional activation of lysosomal exocytosis promotes cellular clearance. (5/9)

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Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases. (6/9)

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Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. (7/9)

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Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency. (8/9)

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