Icariin Inhibits Overexpression and Aggregation of α-Synuclein in A53T α-Synuclein Transgenic Mice by Regulating Parkin and PLK2

¹ Department of Pharmacy, Xuanwu Hospital, Capital Medical University; Beijing Geriatric Medical Research Center; National Center for Neurological Disorders; National Clinical Research Center for Geriatric Diseases; Beijing Institute for Brain Disorders; Beijing Engineering Research Center for Nerve System Drugs; Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 100053 Beijing, China

^*Correspondence: xwzhanglan@126.com (Lan Zhang); linlixw@126.com (Lin Li)

J. Integr. Neurosci. 2023, 22(6), 166; https://doi.org/10.31083/j.jin2206166

Submitted: 25 July 2023 | Revised: 11 September 2023 | Accepted: 27 September 2023 | Published: 23 November 2023

This is an open access article under the CC BY 4.0 license.

Abstract

Background: Synucleinopathies, which are major pathological features of Parkinson’s disease (PD), are characterized by misfolded aggregates of $\alpha{}$ -synuclein in the peripheral and central nervous system. Icariin (ICA) is the main active component of Epimedium flavonoids. Our previous study found that ICA decreases $\alpha{}$ -synuclein expression in APPV717I transgenic mice. Methods: The aim of the present study was to examine the potential applications and mechanisms of ICA in PD using A53T $\alpha{}$ -synuclein transgenic (A53T Tg) mice. After 3 months of intragastric ICA administration, rotarod and pole tests were used to assess behavioral changes in A53T Tg mice at 8 and 13 months of age. SH-SY5Y cells over-expressing wild-type $\alpha{}$ -synuclein were used to further examine the pharmacological effect and underlying mechanism of ICA. Western blotting and immunocytochemistry were used to detect the expression levels of $\alpha{}$ -synuclein and its related proteins. Results: ICA significantly improved the impaired motor function and coordination in A53T Tg mice. It also decreased the expression, Ser129 phosphorylation, and aggregation of $\alpha{}$ -synuclein in SH-SY5Y cells transfected with $\alpha{}$ -synuclein and the striatum of A53T Tg mice. Moreover, ICA increased the expression of parkin, which is associated with the ubiquitin-proteasome system (UPS), and decreased the level of polo-like kinase 2 (PLK2), an enzyme that phosphorylates $\alpha{}$ -synuclein. Conclusions: ICA alleviated motor impairments in A53T mice, an effect which may be associated with the decreased phosphorylation and aggregation of $\alpha{}$ -synuclein through PLK2 and parkin regulation.

Keywords

icariin

synucleinopathy

α-synuclein

motor impairment

parkin

PLK2

Funding

81673406/National Natural Science Foundation of China

82104419/National Natural Science Foundation of China

KM202210025017/R&D Program of Beijing Municipal Education Commission

2013ZZ-25/Incubation Program Beijing Postdoctoral Sustentation Fund of China

PZ2022006/Cultivation Fund of Hospital Management Center in Beijing

DFL20190803/Beijing Hospitals Authority Ascent Plan

20220615ZZ07110074/Science and Technology Think Tank Youth Talent Program

Figures

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Fig. 1.

ICA attenuates behavior dysfunction in young and aged A53T $\alpha{}$ -synuclein transgenic mice. The rotarod and pole tests were applied to assess the motor balance and coordination of the A53T Tg mice after intragastric administration of ICA for 3 months. (A) Time on the rotarod (latency to fall off the rotarod) of the 8-month-old mice in the rotarod test. (B) Time on the rotarod of the 13-month-old mice in the rotarod test. (C) Pole test; time spent climbing down the pole by the 8-month-old mice. (D) Pole test; performance score for climbing down the pole of mice at 13 months of age. Data are provided as the mean $\pm{}$ SEM, n = 4–9 per group (8-month-old mice), n = 9–12 per group (13-month-old mice). *p $<$ 0.05, **p $<$ 0.01, vs. model group. ICA, icariin; SEM, standard error of the mean; Tg (+), A53T $\alpha{}$ -synuclein transgenic mice; WT, wild type.

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