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.
Ying Yang  1 ,  Min Shi PhD  2 ,  Xiaodan Liu  3 ,  Qiaoyun Zhu  4 ,  Zhi Xu  5 ,  Genliang Liu  6 ,  Tao Feng  6 ,  Tessandra Stewart  7 ,  Jing Zhang  8
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. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98104, USA. Electronic address: [email protected].
  • 8. 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: [email protected].
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 (SNCAA53T), 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
Parkinson’s disease; calcium influx; red blood cells; α-synuclein.
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