Lipid induced lysosomal damage after demyelination corrupts microglia protective function in Lysosomal Storage Disorders

ABSTRACT: Neuropathic Lysosomal Storage Disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann Pick disease type A (NPA). We establish that an NPA patient and the Acid Sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build up induces lysosomal damage and Cathepsin B extracellul

SUBMITTER: Dr. Maria Dolores Ledesma 

PROVIDER: S-SCDT-EMBOJ-2018-99553 | biostudies-other |

REPOSITORIES: biostudies-other