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 4

Deletion of AEP attenuates cholestanol-induced α-syn pathology and motor deficits.

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Deletion of AEP attenuates cholestanol-induced α-syn pathology and motor...
WT and Lgmn–/– mice were fed a cholestanol or chow diet 1 month before stereotaxic injection with α-syn PFFs or PBS. The cholestanol treatment lasted during the whole experiment. (A) Rotarod test (n = 6). (B) Pole test (n = 6). (C) Beam-walking test (n = 6). (D) Representative pS129 immunostaining in the cortex, striatum, substantia nigra, and hippocampus of mice sacrificed 6 months after intrastriatal α-syn PFF or PBS injection. Scale bar: 20 μm. (E) Double immunostaining of pS129 and TH in the substantia nigra. The histogram shows the ratio of the pS129 area to the TH area (n = 4 mice/group). Scale bar: 20 μm. (F) Western blot analysis of active-AEP, p-α-syn, total α-syn, TH, and DAT (n = 3 mice per group). (G and H) Representative images of TH-positive fibers in the striatum. The histogram shows the density of TH-positive fibers in the striatum (n = 5 mice per group). Scale bar: 200 μm. (I and J) Representative images of TH-positive neurons in the SNpc. The histogram shows the number of TH-positive neurons in the SNpc (n = 4 to 5 mice/group). Scale bar: 100 μm. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001; compared by 1-way ANOVA with Fisher’s LSD multiple comparison test. Ctr; control chow diet; Cho, cholestanol; Ctx, cortex; ST, striatum; SN, substantia nigra; Hip, hippocampus.