The analysis of a mouse model of Lysosomal Storage Disorder uncovers a role for astrocyte dysfunction in neurodegeneration

Di Malta, Chiara (2012). The analysis of a mouse model of Lysosomal Storage Disorder uncovers a role for astrocyte dysfunction in neurodegeneration. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000d4e7

Abstract

Astrocytes are the most abundant cellular population in the brain and their role in neurodegenerative processes is becoming increasingly appreciated. In my PhD project, I investigated the contribution of astrocytes to neurodegeneration in Multiple Sulfatase Deficiency (MS D), a severe Lysosomal Storage Disorder (LSD) caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene. Using Cre/Lox mouse models, I found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of toxic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo, whereas other neuronal populations were spared. Furthermore, in an ex vivo co-culture assay, I observed that Sumf1-/- astrocytes failed to support the survival and function of wild type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration in LSDs. Compared to the astrocyte-specific deletion of Sumf1, the concomitant deletion of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioural analysis of mice with astrocyte-specific deletion of Sumf1 compared to mice with Sumf1 deletion in both astrocytes and neurons allowed me to link a subset of neurological manifestations of LSDs to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in LSDs and that modulation of astrocyte function may impact the disease course.

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