Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane

Naohito Ito; Mayumi Tsuji; Naoki Adachi; Shiro Nakamura; Avijite Kumer Sarkar; Kensuke Ikenaka; César Aguirre; Atsushi Michael Kimura; Yuji Kiuchi; Hideki Mochizuki; David B Teplow; Kenjiro Ono

doi:10.1038/s41531-023-00583-0

Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane

NPJ Parkinsons Dis. 2023 Sep 28;9(1):139. doi: 10.1038/s41531-023-00583-0.

Authors

Naohito Ito^{1

2}, Mayumi Tsuji³, Naoki Adachi⁴, Shiro Nakamura⁵, Avijite Kumer Sarkar⁶, Kensuke Ikenaka⁷, César Aguirre⁷, Atsushi Michael Kimura⁸, Yuji Kiuchi^{1

9}, Hideki Mochizuki⁷, David B Teplow¹⁰, Kenjiro Ono¹¹

Affiliations

¹ Department of Pharmacology, School of Medicine, Showa University, Tokyo, 142-8555, Japan.
² Department of Internal Medicine, Division of Neurology, School of Medicine, Showa University, Tokyo, 142-8666, Japan.
³ Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan. tsujim@med.showa-u.ac.jp.
⁴ Department of Physiology, School of Medicine, Showa University, Tokyo, 142-8555, Japan.
⁵ Department of Oral Physiology, School of Dentistry, Showa University, Tokyo, 142-8555, Japan.
⁶ Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229-3026, USA.
⁷ Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
⁸ Brain Research Institute Center for Integrated Human Brain Science, Department of Functional Neurology and Neurosurgery, Niigata University, Niigata, 951-8122, Japan.
⁹ Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan.
¹⁰ Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles (UCLA), Los Angeles, LA, 10833, USA.
¹¹ Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan. onoken@med.kanazawa-u.ac.jp.

Abstract

α-Synuclein (αS), the causative protein of Parkinson's disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Abstract

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