Increased expression of coronin-1a in amyotrophic lateral sclerosis: a potential diagnostic biomarker and therapeutic target

doi:10.1007/s11684-021-0905-y

Front. Med.

2022, Vol. 16

Issue (5) : 723-735 https://doi.org/10.1007/s11684-021-0905-y

RESEARCH ARTICLE

Increased expression of coronin-1a in amyotrophic lateral sclerosis: a potential diagnostic biomarker and therapeutic target

Qinming Zhou¹, Lu He¹, Jin Hu², Yining Gao¹, Dingding Shen^1,³, You Ni¹, Yuening Qin⁴, Huafeng Liang⁵, Jun Liu¹(

), Weidong Le⁶(

), Sheng Chen^1,³(

)

¹. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
². Department of Neurology, the First Hospital of Jiaxing & the Affiliated Hospital of Jiaxing University, Jiaxing 314000, China;
³. Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226007, China;
⁴. Department of Dermatology, The People’s Hospital of Rushan, Weihai 264500, China;
⁵. Department of Neurology, Xinrui Hospital, Wuxi 214000, China;
⁶. Institute of Neurology, Sichuan Academy of Medical Sciences-Sichuan Provincial Hospital, Chengdu 610072, China

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Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. At present, no definite ALS biomarkers are available. In this study, exosomes from the plasma of patients with ALS and healthy controls were extracted, and differentially expressed exosomal proteins were compared. Among them, the expression of exosomal coronin-1a (CORO1A) was 5.3-fold higher than that in the controls. CORO1A increased with disease progression at a certain proportion in the plasma of patients with ALS and in the spinal cord of ALS mice. CORO1A was also overexpressed in NSC-34 motor neuron-like cells, and apoptosis, oxidative stress, and autophagic protein expression were evaluated. CORO1A overexpression resulted in increased apoptosis and oxidative stress, overactivated autophagy, and hindered the formation of autolysosomes. Moreover, CORO1A activated Ca²⁺-dependent phosphatase calcineurin, thereby blocking the fusion of autophagosomes and lysosomes. The inhibition of calcineurin activation by cyclosporin A reversed the damaged autolysosomes. In conclusion, the role of CORO1A in ALS pathogenesis was discovered, potentially affecting the disease onset and progression by blocking autophagic flux. Therefore, CORO1A might be a potential biomarker and therapeutic target for ALS.

Keywords amyotrophic lateral sclerosis coronin-1a autophagy pathogenesis

Corresponding Author(s): Jun Liu,Weidong Le,Sheng Chen

Just Accepted Date: 29 March 2022 Online First Date: 06 June 2022 Issue Date: 18 November 2022

Cite this article:

Qinming Zhou,Lu He,Jin Hu, et al. Increased expression of coronin-1a in amyotrophic lateral sclerosis: a potential diagnostic biomarker and therapeutic target[J]. Front. Med., 2022, 16(5): 723-735.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0905-y
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/723

Tab.1 Twenty top hit candidates in the proteomic analysis of exosomal proteins

Fig.1 CORO1A expression in human plasma and spinal cord of SOD1-G93A mice. (A, C) Western blot and quantitative analysis of the CORO1A expression in human plasma (ALS, patients with ALS; NC, normal controls; n = 3, P = 0.0087). (B, D) Western blot and quantitative analysis of the CORO1A expression in the spinal cord of SOD1-G93A mice. NC, wild-type mice; 4W, 4 weeks old; 8W, 8 weeks old; 12W, 12 weeks old; DIE, death; P = 0.0092 (8W vs. NC), P = 0.0035 (12W vs. NC), P = 0.0012 (DIE vs. NC), n = 5. (E) CORO1A expression in human plasma by ELISA (n = 30, P < 0.0001). (F) CORO1A expression in SOD-G93A mice by ELISA (n = 5). (G) CORO1A expression increased with disease progression in the plasma of 8 of 10 patients with ALS, as detected by ELISA. *P < 0.05, **P < 0.01, and ****P < 0.0001 vs. the NC group.

Fig.2 Effect of CORO1A on the apoptosis of NSC-34 cells. (A) Photomicrographs of TUNEL staining in NSC-34 cells (Blue, DAPI; red, TUNEL). Scale bar = 50 μm. (B) Density of TUNEL staining in NSC-34 cells (n = 10). *P < 0.05 and **P < 0.01 vs. the NC group, ^#P < 0.05 vs. the OE group.

Fig.3 Effect of CORO1A on the oxidative stress level in NSC-34 cells. (A) ROS level detection in the OE group. (B) ROS level detection in the SH group. (C) ROS level detection in the NC group. The oxidative stress level in the OE group was higher than that in the SH and NC groups. X-axis, fluorescence intensity; Y-axis, cell count.

Fig.4 Effect of CORO1A on the expression of autophagic proteins. (A) Expression of CORO1A, LC3II, p62, Beclin-1, and CaN by western blot. (B−F) Quantification of the expression of CORO1A, LC3II, p62, Beclin-1, and CaN, respectively. CORO1A: P = 0.0037 (OE vs. NC), P = 0.0083 (SH vs. NC). LC3II: P = 0.0075 (OE vs. NC), P = 0.83 (SH vs. NC). p62: P = 0.0002 (OE vs. NC), P = 0.018 (SH vs. NC). Beclin-1: P = 0.0090 (OE vs. NC), P = 0.029 (SH vs. NC). CaN: P = 0.0014 (OE vs. NC), P = 0.043 (SH vs. NC). *P < 0.05, **P < 0.01 vs. the NC group.

Fig.5 Effect of CORO1A on the autophagy of NSC-34 cells. (A) Photomicrographs of LC3II immunostaining, scale bar = 5 μm (Blue, DAPI; green, LC3II; red, LAMP1), scale bar = 5 μm (DAPI, LC3, and Merge), scale bar = 2 μm (Enlarge). (B) Co-staining of LC3II and LAMP1, scale bar = 10 μm (Blue, DAPI; green, LC3II; red, LAMP1). (C) Quantification of LC3II immunofluorescence, n = 10 in each group. (D) ALs/AVs ratio, n = 10 in each group. *P < 0.05 and **P < 0.01 vs. the NC group. ^#P < 0.05 and ^##P < 0.01 vs. the OE group.

Fig.6 Effect of CsA on the expression of autophagic proteins. (A) Expression of CaN, LC3II, p62, and Beclin-1 by Western blot. (B−E) Quantification of the expression of CaN, LC3II, p62, and Beclin-1 (n = 5). *P < 0.05, **P < 0.01 vs. the OE group.

Fig.7 Potential role of CORO1A in the pathogenesis of ALS. Exosomes were extracted from the plasma of patients with ALS and healthy controls, and the proteomic analysis was performed, CORO1A was selected among the differentially expressed proteins. The expression of CORO1A increased with the progression of the disease in 8 of the 10 selected patients with ALS, as demonstrated by its content in the plasma and in the spinal cord of ALS mice. Thus, CORO1A could be considered as a potential biomarker for ALS. The function of CORO1A was further explored using NSC-34 cells. The overexpression of CORO1A in NSC-34 cells over-activated autophagy, blocked the autophagic flux, increased apoptosis and oxidative stress damage, finally leading to motor neuron degeneration.

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