Min-Kyung Nam1, Ji-Hye Han1, Ja-Young Jang2, Si-Eun Yun1, Goo-Young Kim1, Seongman Kang2, Hyangshuk Rhim3. 1. Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. 2. Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea. 3. Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea. Electronic address: hrhim@catholic.ac.kr.
Abstract
BACKGROUND: Genetic studies and the abundance of alpha-synuclein (α-Syn) in presynaptic terminals suggest that α-Syn plays a critical role in maintaining synaptic vesicle pools. However, there are still few experimental tools for elucidating its physiological roles. METHODS: Unexpectedly, we detected various cellular distribution patterns of endogenous α-Syn by immunofluorescence assays (IFAs). To provide new molecular insights into α-Syn research, we identified associations between epitopes, conformations, and subcellular localization of α-Syn and categorized them. RESULTS: The α-Syn exposing Y125 was found to coexist with F-actin at the edge of the cells, including the plasma membrane. α-Syn conformations exposing P128 or both F94 and K97 were partly localized to the mitochondria. These results indicate that various conformations of α-Syn are associated with specific subcellular localizations. Intriguingly, we demonstrate for the first time that the phosphorylated α-Syn at Ser129, also known as a Parkinson's disease (PD)-causing form, is targeted to the mitochondria. CONCLUSIONS: Our study showed that different subcellular distribution patterns of α-Syn reflect the existence of various α-Syn conformations under normal conditions. GENERAL SIGNIFICANCE: This study provides novel clues for deciphering the physiological function of α-Syn in connection with subcellular localization. Dissecting the specific α-Syn conformations may lead to useful strategies in PD therapy and diagnosis.
BACKGROUND: Genetic studies and the abundance of alpha-synuclein (α-Syn) in presynaptic terminals suggest that α-Syn plays a critical role in maintaining synaptic vesicle pools. However, there are still few experimental tools for elucidating its physiological roles. METHODS: Unexpectedly, we detected various cellular distribution patterns of endogenous α-Syn by immunofluorescence assays (IFAs). To provide new molecular insights into α-Syn research, we identified associations between epitopes, conformations, and subcellular localization of α-Syn and categorized them. RESULTS: The α-Syn exposing Y125 was found to coexist with F-actin at the edge of the cells, including the plasma membrane. α-Syn conformations exposing P128 or both F94 and K97 were partly localized to the mitochondria. These results indicate that various conformations of α-Syn are associated with specific subcellular localizations. Intriguingly, we demonstrate for the first time that the phosphorylated α-Syn at Ser129, also known as a Parkinson's disease (PD)-causing form, is targeted to the mitochondria. CONCLUSIONS: Our study showed that different subcellular distribution patterns of α-Syn reflect the existence of various α-Syn conformations under normal conditions. GENERAL SIGNIFICANCE: This study provides novel clues for deciphering the physiological function of α-Syn in connection with subcellular localization. Dissecting the specific α-Syn conformations may lead to useful strategies in PD therapy and diagnosis.
Authors: Anke Van der Perren; Géraldine Gelders; Alexis Fenyi; Ronald Melki; Veerle Baekelandt; Luc Bousset; Filipa Brito; Wouter Peelaerts; Chris Van den Haute; Steve Gentleman Journal: Acta Neuropathol Date: 2020-04-30 Impact factor: 17.088