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

Abstract

Neuropathic lysosomal storage disorders ( LSD s) 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 ( ASM ko) mouse model show amoeboid microglia in neurodegeneration‐prone areas. In vivo microglia ablation worsens disease progression in ASM ko mice. We demonstrate the coexistence of different microglia phenotypes in ASM ko 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 ASM ko 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 LSD s 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 LSD s and other demyelinating diseases.

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

“…Microglia are responsible for the neuroinflammatory phenotype that occurs in brains of Npc1 -/mice as infiltration of peripheral macrophages could not be detected in this model (Cho, Vardi et al, 2018, Cougnoux et al, 2018. However, the contribution of microglial activation to neurodegeneration in NPC is still being discussed (Baudry et al, 2003, Gabande-Rodriguez et al, 2018, Lopez et al, 2011, Peake et al, 2011, Pressey et al, 2012. In accordance with previous reports (Baudry et al, 2003, Cougnoux et al, 2018, we detected pronounced microglial reactivity throughout cortex and hippocampus prior to neuronal loss.…”

“…We found that in cerebellum ( Fig 3B), cortex ( Fig 3C) and the hippocampus ( Fig EV6A) of symptomatic Npc1 -/mice almost all CD68 positive cells accumulated Fluoromyelin intracellularly. Similarly, myelin accumulation was detected within microglia of symptomatic Npc-deficient mice (Gabande-Rodriguez, Perez-Canamas et al, 2018). Importantly, our proteomic analysis identified increased levels of a myelin specific protein (e.g., proteolipid protein 1, PLP1) and protein involved in microglial phagocytosis of myelin (e.g., galectin 3/LGALS3) in Npc1 -/microglia already at pre-symptomatic stages ( Fig 2C, Table EV2).…”

“…Microglia control OPC recruitment and differentiation (Domingues, Portugal et al, 2016, Miron, 2017 and are responsible for the clearance of myelin debris. Impaired removal of myelin debris by microglia can heavily compromise re-myelination upon injury (Cantuti-Castelvetri et al, 2018, Gabande-Rodriguez et al, 2018. Hypomyelination phenotype described in NPC mouse models and human patients has been mainly associated to a cell autonomous impairment of oligodendrocytes (Kodachi, Matsumoto et al, 2017, Qiao et al, 2018, Takikita et al, 2004, Weintraub et al, 1987, Weintraub et al, 1985, Yu & Lieberman, 2013.…”

“…While cell culture experiments suggested that Npc1 -/microglia do not directly trigger neurotoxicity (Peake, Campenot et al, 2011) and microglial ablation in an NPC murine model was not beneficial (Gabande-Rodriguez, Perez-Canamas et al, 2018), additional studies supported beneficial effects of microglial modulation (Cougnoux et al, 2018, Smith et al, 2009, Williams, Wallom et al, 2014. Moreover, significant changes in inflammatory markers were reported in both pre-symptomatic murine model and human NPC cases, suggesting that immune response could be a precocious phenomenon preceding neuronal loss (Baudry et al, 2003, Cluzeau, Watkins-Chow et al, 2012, Cologna et al, 2014, Pressey, Smith et al, 2012.…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…Indeed, molecular evidence of microgliosis has been well established in mouse and dog models of MPS I and MPS III A, B, and C subtypes [166,182,188,190]. Inhibition of CTSB has been shown to prevent neuronal death and behavioral disorders in a patient affected by the Niemann-Pick disease type A and in a mouse model of the disease [191]. Although further studies are needed to fully elucidate the pathophysiological role of CTSs in the CNS, the above findings strongly suggest that the specific inhibition of microglial CTSs might lead to neuroprotective outcomes in MPS phenotypes characterized by activated pro-inflammatory microglia.…”