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

Autor: Ito N; Department of Pharmacology, School of Medicine, Showa University, Tokyo, 142-8555, Japan.; Department of Internal Medicine, Division of Neurology, School of Medicine, Showa University, Tokyo, 142-8666, Japan., Tsuji M; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan. tsujim@med.showa-u.ac.jp., Adachi N; Department of Physiology, School of Medicine, Showa University, Tokyo, 142-8555, Japan., Nakamura S; Department of Oral Physiology, School of Dentistry, Showa University, Tokyo, 142-8555, Japan., Sarkar AK; Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229-3026, USA., Ikenaka K; Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan., Aguirre C; Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan., Kimura AM; Brain Research Institute Center for Integrated Human Brain Science, Department of Functional Neurology and Neurosurgery, Niigata University, Niigata, 951-8122, Japan., Kiuchi Y; Department of Pharmacology, School of Medicine, Showa University, Tokyo, 142-8555, Japan.; Pharmacological Research Center, Showa University, Tokyo, 142-8555, Japan., Mochizuki H; Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan., Teplow DB; Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles (UCLA), Los Angeles, LA, 10833, USA., Ono K; Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan. onoken@med.kanazawa-u.ac.jp.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2023 Sep 28; Vol. 9 (1), pp. 139. Date of Electronic Publication: 2023 Sep 28.
DOI: 10.1038/s41531-023-00583-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: