Abstract
Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the Npc1 gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. While it has been shown that inflammation precedes and exacerbates symptom severity in NPC1 disease, it is unclear whether oxLDL contributes to NPC1 disease progression. In this study, we investigated the effects of increasing anti-oxLDL IgM autoantibodies on systemic and neurological symptoms in an NPC1 disease mouse model. For this purpose, Npc1nih mice were immunized with heat-inactivated S. pneumoniae, an immunogen which elicits an IgM autoantibody-mediated immune response against oxLDL. Npc1nih mice injected with heat-inactivated pneumococci displayed an improved hepatic phenotype, including liver lipid accumulation and inflammation. In addition, regression of motor skills was delayed in immunized Npc1nih. In line with these results, brain analyses showed an improved cerebellar phenotype and neuroinflammation in comparison with control-treated subjects. This study highlights the potential of the pneumococcal immunization as a novel therapeutical approach in NPC1 disease. Future research should investigate whether implementation of this therapy can improve life span and quality of life of NPC1 disease patients.
Highlights
Niemann-Pick type C1 (NPC1) disease is a rare, fatal disorder caused by mutations in the Npc1 gene which result in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes/early lysosomes [1,2,3]
To determine whether antioxLDL IgM autoantibodies have a protective effect in NPC1, 2 week-old Npc1nih mice were immunized with heat-inactivated pneumococci, known to induce high anti-oxidized low-density lipoprotein (oxLDL) IgM titers dominated by T15-idiotypic IgM [18, 31]
We show that heat-inactivated pneumococci immunization improves both systemic and neurological symptoms, including motor function, neurodegeneration, neuro- and systemic inflammation in a mouse model of NPC1 disease
Summary
Niemann-Pick type C1 (NPC1) disease is a rare, fatal disorder caused by mutations in the Npc gene which result in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes/early lysosomes [1,2,3]. Multiple research papers have described the cholesterol oxidation products 7-ketocholesterol and cholestane3β, 5α, 6β-triol, two products abundantly present in oxLDL [21, 22], as sensitive and specific blood-based biomarkers for diagnosing NPC1 disease [6, 23, 24]. Whether these cholesterol oxidation products contribute to NPC1 disease progression has to our knowledge never been investigated
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