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

Enrique Gabandé‐Rodríguez,Héctor Peinado,Sara Sánchez‐Redondo,Azucena Pérez‐Cañamás,Daniel N Mitroi,María Dolores Ledesma,César Venero,Elena Martínez‐Sáez,Beatriz Soto‐Huelin

doi:10.15252/embj.201899553

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 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.

Highlights

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia
Our findings unexpectedly identify a subpopulation of microglia as a dominant factor that mediates Niemann–Pick disease type A (NPA) pathology, with a protective function that is corrupted after lysosomal damage
We found diffuse CathB staining in a significant percentage (21.98%) of ionised calcium-binding adaptor molecule 1 (Iba-1)-positive cells in the Cb from acid sphingomyelinase knockout (ASMko) but not wt mice, which further supports the occurrence of lysosomal membrane permeabilisation (LMP) in ASMko microglia (Fig 4G)

Summary

Introduction

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. 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. 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

Methods

Results

Conclusion