title: Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder.
abstract: The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1(-/-) astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.
authors: Telethon Institute of Genetics and Medicine, 80131 Naples,  Italy.
authors: Chiara
authors: C
authors: Di Malta
authors: John D
authors: JD
authors: Fryer
authors: Carmine
authors: C
authors: Settembre
authors: Andrea
authors: A
authors: Ballabio
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D020140:Lysosomal Storage Diseases, Nervous System / Q000235:genetics / Q000473:pathology; D008247:Lysosomes / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011689:Purkinje Cells / Q000473:pathology / Q000648:ultrastructure; D013429:Sulfatases / Q000235:genetics*
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; C519507:Sumf1 protein, mouse; D013429:Sulfatases