Evaluation of the Potential Role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Niemann–Pick Disease, Type C1

• Main Authors: Niamh X. Cawley, Anna T. Lyons, Daniel Abebe, Christopher A. Wassif, Forbes D. Porter
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: International Journal of Molecular Sciences
• Subjects: Niemann–Pick C; PCSK9; neurodegeneration; VLDLR; ApoER2; lysosomal storage
• Online Access: https://www.mdpi.com/1422-0067/21/7/2430

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 <i>Reeler</i> mouse. Our recent findings that <i>Pcsk9</i> 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 <i>Pcsk9^-/-/Npc1^-/-</i> mice by disease severity scoring, motor assessments, lifespan, and cerebellar Purkinje cell staining, showed no obvious difference in NPC1 disease progression with that of <i>Npc1^-/-</i> mice. This suggests that PCSK9 does not play an apparent role in NPC1 disease progression.