Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

• Enrique Gabandé‐Rodríguez ^[3] ; Azucena Pérez‐Cañamás ^[4] ; Beatriz Soto‐Huelin ^[1] ; Daniel N Mitroi ^[1] ; Sara Sánchez‐Redondo ^[5] ; Elena Martínez‐Sáez ^[6] ; César Venero ^[2] ; Héctor Peinado ^[7] ; María Dolores Ledesma ^[1]
  1. [1] Centro de Biología Molecular Severo Ochoa

     Centro de Biología Molecular Severo Ochoa

     Madrid, España

     
  2. [2] Universidad Nacional de Educación a Distancia

     Universidad Nacional de Educación a Distancia

     Madrid, España

     
  3. [3] 1 Department of Molecular Neuropathology Centro de Biología Molecular “Severo Ochoa” (CSIC‐UAM) Madrid Spain; 2 Barts Cancer Institute Centre for Cancer & Inflammation Queen Mary University of London London UK
  4. [4] 1 Department of Molecular Neuropathology Centro de Biología Molecular “Severo Ochoa” (CSIC‐UAM) Madrid Spain; 7Present address: Cellular Neuroscience, Neurodegeneration and Repair Program Department of Neurology Yale University School of Medicine New Haven CT USA
  5. [5] 3 Microenvironment and Metastasis Group Molecular Oncology Program Spanish National Cancer Research Centre (CNIO) Madrid Spain
  6. [6] 4 Department of Pathology Hospital Universitario Vall d′Hebron Barcelona Spain
  7. [7] 3 Microenvironment and Metastasis Group Molecular Oncology Program Spanish National Cancer Research Centre (CNIO) Madrid Spain; 6 Department of Pediatrics Drukier Institute for Children's Health and Meyer Cancer Center Weill Cornell Medical College New York NY USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 2, 2019, pág. 1
• Idioma: inglés
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  • 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 extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann–Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.