Abstract
Niemann–Pick disease, type C1, is a cholesterol storage disease where unesterified cholesterol accumulates intracellularly. In the cerebellum this causes neurodegeneration of the Purkinje neurons that die in an anterior-to-posterior and time-dependent manner. This results in cerebellar ataxia as one of the major outcomes of the disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a significant role in the regulation of serum cholesterol levels by modulating LDL receptor levels on peripheral tissues. In the central nervous system, PCSK9 may have a similar effect on the closely related VLDL and ApoE2 receptors to regulate brain cholesterol. In addition, regulation of VLDLR and ApoER2 by PCSK9 may contribute to neuronal apoptotic pathways through Reelin, the primary ligand of VLDLR and ApoER2. Defects in reelin signaling results in cerebellar dysfunction leading to ataxia as seen in the Reeler mouse. Our recent findings that Pcsk9 is expressed ~8-fold higher in the anterior lobules of the cerebellum compared to the posterior lobule X, which is resistant to neurodegeneration, prompted us to ask whether PCSK9 could play a role in NPC1 disease progression. We addressed this question genetically, by characterizing NPC1 disease in the presence or absence of PCSK9. Analysis of double mutant Pcsk9-/-/Npc1-/- mice by disease severity scoring, motor assessments, lifespan, and cerebellar Purkinje cell staining, showed no obvious difference in NPC1 disease progression with that of Npc1-/- mice. This suggests that PCSK9 does not play an apparent role in NPC1 disease progression.
Highlights
Niemann–Pick disease, type C (NPC) is an autosomal recessive, lysosomal storage disorder that affects ~1:120,000 births [1,2]
Patients with NPC initially present with hepatosplenomegaly that is followed by progressive neurodegeneration leading to cerebellar ataxia and dementia [1,3] with patients typically succumbing to the disease in the second decade of life [4]
NPC is caused by mutations in NPC1 or NPC2, which encode for proteins that are involved in the transport of unesterified cholesterol out of the lysosome [5,6,7,8]
Summary
Niemann–Pick disease, type C (NPC) is an autosomal recessive, lysosomal storage disorder that affects ~1:120,000 births [1,2]. Patients with NPC initially present with hepatosplenomegaly that is followed by progressive neurodegeneration leading to cerebellar ataxia and dementia [1,3] with patients typically succumbing to the disease in the second decade of life [4]. NPC is caused by mutations in NPC1 or NPC2, which encode for proteins that are involved in the transport of unesterified cholesterol out of the lysosome [5,6,7,8]. While much is known about the cause of NPC and the disease progression, there remains a need for a greater understanding of the molecular processes and pathways involved in the patterned neurodegeneration of the Purkinje neurons in order to develop new therapies
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