Calcium influx: An essential process by which α-Synuclein regulates morphology of erythrocytes

Ying Yang; Min Shi; Xiaodan Liu; Qiaoyun Zhu; Zhi Xu; Genliang Liu; Tao Feng; Tessandra Stewart; Jing Zhang

doi:10.1016/j.jare.2023.09.009

Calcium influx: An essential process by which α-Synuclein regulates morphology of erythrocytes

J Adv Res. 2023 Sep 13:S2090-1232(23)00257-6. doi: 10.1016/j.jare.2023.09.009. Online ahead of print.

Authors

Ying Yang¹, Min Shi², Xiaodan Liu³, Qiaoyun Zhu⁴, Zhi Xu⁵, Genliang Liu⁶, Tao Feng⁷, Tessandra Stewart⁸, Jing Zhang⁹

Affiliations

¹ Department of Pathology, Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou, Zhejiang 310002, China; Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
² Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA.
³ Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
⁴ Central Laboratory, Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou, Zhejiang 310002, China.
⁵ Department of Pathology, Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou, Zhejiang 310002, China.
⁶ Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing 100070, China.
⁷ Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China; China National Clinical Research Center for Neurological Diseases, Beijing 100070, China. Electronic address: happyft@sina.com.
⁸ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98104, USA. Electronic address: stewarth@uw.edu.
⁹ Department of Pathology, Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou, Zhejiang 310002, China; National Human Brain Bank for Health and Disease, Zhejiang University, Zhejiang, Hangzhou, China. Electronic address: jzhang1989@zju.edu.cn.

PMID: 37714326
DOI: 10.1016/j.jare.2023.09.009

Abstract

Introduction: Morphological abnormalities of erythrocytes/red blood cells (RBCs), e.g., increased acanthocytes, in Parkinson's disease (PD) have been reported previously, although the underlying mechanisms remain to be characterized. In this study, the potential roles of α-synuclein (α-syn), a protein critically involved in PD and highly abundant in RBCs, were studied in PD patients as well as in a PD mouse model.

Methods: Transgenic [PAC-Tg (SNCA^A53T), A53T] mice overexpressing A53T mutant α-syn and SNCA knockout mice were employed to characterize the effect of α-syn on RBC morphology. In addition to A53T and SNCA knockout mice, the morphology of RBCs of PD patients was also examined using scanning electron microscopy. The potential roles of α-syn were further investigated in cultured RBCs and mice.

Results: Morphological abnormalities of RBCs and increased accumulation of aggregated α-syn on the RBC membrane were observed in PD patients. A similar phenomenon was also observed in A53T mice. Furthermore, while mice lacking α-syn expression showed a lower proportion of acanthocytes, treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. In a follow-up proteomic investigation, several major classes of proteins were identified as α-syn-associated proteins on the RBC membrane, seven of which were calcium-binding proteins. Applying aggregated α-syn to the RBC membrane directly induced extracellular calcium influx along with morphological changes; both observations were adequately reversed by blocking calcium influx.

Conclusions: This study demonstrated that α-syn plays a critical role in PD-associated morphological abnormalities of RBCs, at least partially via a process mediated by extracellular calcium influx.

Keywords: Calcium influx; Parkinson’s disease; Red blood cells; α-synuclein.