Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase
Ting Yu, Shuke Nie, Lihong Bu, Miao Liu, Juanfeng He, Xuan Niu, Hongyan Feng, Jifeng Guo, Beisha Tang, Zhaohui Zhang, Keqiang Ye, Haiqiang Jiang, Liam Chen, Zhentao Zhang
Ting Yu, Shuke Nie, Lihong Bu, Miao Liu, Juanfeng He, Xuan Niu, Hongyan Feng, Jifeng Guo, Beisha Tang, Zhaohui Zhang, Keqiang Ye, Haiqiang Jiang, Liam Chen, Zhentao Zhang
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Research Article Neuroscience

Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase

Abstract

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson’s disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.

Authors

Ting Yu, Shuke Nie, Lihong Bu, Miao Liu, Juanfeng He, Xuan Niu, Hongyan Feng, Jifeng Guo, Beisha Tang, Zhaohui Zhang, Keqiang Ye, Haiqiang Jiang, Liam Chen, Zhentao Zhang

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Figure 2

Cholestanol promotes α-syn aggregation by activating AEP.

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Cholestanol promotes α-syn aggregation by activating AEP. (A) Cholestano...
(A) Cholestanol promotes α-syn aggregation induced by α-syn PFFs in α-syn–HEK293 cells. Scale bar: 20 μm. (B) α-Syn aggregates colocalize with pS129 in α-syn–HEK293 cells. The histogram shows the percentage of cells containing α-syn aggregates (n = 10 independent experiments). Scale bars: 20 μm. (C) Representative IBs of pS129 and total α-syn in the Triton X-100–soluble and Triton X-100–insoluble fractions in α-syn–HEK293 cells. (D) Cholestanol promotes α-syn hyperphosphorylation in primary neurons (n = 5 independent experiments). Scale bar: 20 μm. (E) Western blot analysis of Cox IV, AEP, AEP-generated α-syn N103 fragment, p-α-syn, total α-syn, Bcl-2, and Bax induced by cholestanol in α-syn–HEK293 cells. (F) α-Syn aggregates colocalize with pS129 in α-syn–HEK293 cells transfected with sh-LGMN. The histogram shows the percentage of cells containing α-syn aggregates (n = 5–7 independent experiments). Scale bars: 20 μm. (G) Western blots showing the effect of cholestanol on AEP, AEP-generated α-syn N103 fragment, p-α-syn, total α-syn, Bcl-2, and Bax in α-syn–HEK293 cells transfected with sh-LGMN. (H) pS129 immunostaining in WT and Lgmn–/– primary neurons. The histogram shows the ratio of the pS129 area to the MAP2 area (n = 5 independent experiments). Scale bar: 20 μm. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001; 1-way ANOVA with Tukey’s multiple comparison test. TX, Triton X-100. NC, negative control.