Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease

Abstract

Niemann-Pick type C (NPC) disease is a rare progressive lysosomal lipid storage disorder that manifests with a heterogeneous spectrum of clinical syndromes, including visceral, neurological and psychiatric symptoms. This monogenetic autosomal recessive disease is largely caused by mutations in the NPC1 gene, which controls intracellular lipid homeostasis. Vesicle-mediated endo-lysosomal lipid trafficking and non-vesicular lipid exchange via inter-organelle membrane contact sites are both regulated by the NPC1 protein. Loss of NPC1 function therefore triggers intracellular accumulation of diverse lipid species, including cholesterol, glycosphingolipids, sphingomyelin and sphingosine. The NPC1-mediated dysfunction of lipid transport has severe consequences for all brain cells, leading to neurodegeneration. Besides the cell-autonomous contribution of neuronal NPC1, aberrant NPC1 signalling in other brain cells is critical for the pathology. We discuss here the importance of endo-lysosomal dysfunction and a tight crosstalk between neurons, oligodendrocytes, astrocytes and microglia in NPC pathology. We strongly believe that a cell-specific rescue may not be sufficient to counteract the severity of the NPC pathology, but targeting common mechanisms, such as endo-lysosomal and lipid trafficking dysfunction, may ameliorate NPC pathology. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Keywords: NPC1; cholesterol; endo-lysosomal trafficking; glia; neurons.

Figure 1.

Endo-lysosomal dysfunction causes severe clinical manifestations in Niemann–Pick type C disease. NPC1 (transmembrane protein) and NPC2 (luminal protein) regulate intracellular lipid transport. The hydrophobic handoff model hypothesizes that NPC2 transfers cholesterol to the N-terminal domain of NPC1 [9,10]. Lack of NPC1 or NPC2 impairs the cholesterol egress from the late endo-lysosomal compartment, leading to aberrant lipid storage within the organelles. NPC patients manifest with heterogeneous clinical presentations and disease severity. Dependent on the age of disease manifestation, several forms are acknowledged: early infantile (2 months to <2 years); late infantile (2 to 6 years); juvenile (6 to 15 years) and adult (>15 years). ER: endoplasmic reticulum; MCS: membrane contact sites; LE: late endosome; MVB: multivesicular body; lys: lysosome; NTD: N-terminal domain; CTD: C-terminal domain; NPC1: Niemann-Pick type C intracellular cholesterol transporter 1; NPC2: Niemann-Pick type C intracellular cholesterol transporter 2. Based on reported clinical presentations [3,7]. Created with BioRender.com.

Figure 2.

Endo-lysosomal trafficking and neuronal–glial crosstalk in NPC disease. Neuropathology of NPC includes aberrations in endo-lysosomal trafficking and autophagy that have severe functional consequences for brain cell homeostasis, as illustrated by a broad range of pathological hallmarks observed in neurons, oligodendrocytes, microglia and astrocytes. (a) Endocytosis of HDL-like particles is mediated by membrane proteins of the LDLR gene family. Following membrane invagination, LDLRs are recycled to the cell surface while lipids, such as cholesterol, are transported to LE/lys for further processing. Unesterified (free) cholesterol is exported from LE/lys to ER, where it is esterified and stored in lipid droplets. (b) Loss of NPC1 results in trafficking impairments, leading to accumulation of cholesterol in LE/MVBs, precluding cholesterol export, esterification at the ER and incorporation into lipid droplets. EE: early endosome; LE: late endosome; MVB: multivesicular body; lys: lysosome; ER: endoplasmic reticulum; HDL: high-density lipoprotein; LDLR: low-density lipoprotein receptor; LD: lipid droplet; NPC1: Niemann–Pick type C intracellular cholesterol transporter 1.