Mitochondrial dysfunction has been linked to neurodegenerative disorders such as Parkinson disease. However it is likely that there are also other important players in neurodegenerative processes and that these players may differ in different neurodegenerative diseases. In this study the authors investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency, a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (Sumf1) gene.
The authors found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with cytoplasmic accumulation of autophagic substrates. Degeneration of cortical neurons was observed in vivo. In ex vivo coculture assays, Sumf1deficient astrocytes failed to support the survival and function of wild-type cortical neurons. 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.
Behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed the authors to link a subset of neurological manifestations of multiple sulfatase deficiency disease to astrocyte dysfunction. Astrocytes appear to be integral components of the neuropathology in multiple sulfatase deficiency disease. The authors suggest that modulation of astrocyte function may impact disease course.
Di Malta C, Fryer JD, Settembre C, and Ballabio A: Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. Proc. Natl. Acad. Sci. USA [Epub ahead of print July 23, 2012, doi: 10.1073/pnas.1209577109]