title: High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction.
abstract: To clarify the role of α-synuclein (αSyn) in neuronal membrane remodeling, we analyzed the expression of αSyn in neurons with a dysfunction of PLA2G6, which is indispensable for membrane remodeling. αSyn/phosphorylated-αSyn (PαSyn) distribution and neurodegeneration were quantitatively estimated in PLA2G6-knockout (KO) mice, which demonstrate marked mitochondrial membrane degeneration. We also assessed the relationship between αSyn deposits and mitochondria in brain tissue from patients with PLA2G6-associated neurodegeneration (PLAN) and Parkinson's disease (PD), and quantitatively examined Lewy bodies (LBs) and neurons. The expression level of αSyn was elevated in PLA2G6-knockdown cells and KO mouse neurons. Strong PαSyn expression was observed in neuronal granules in KO mice before onset of motor symptoms. The granules were mitochondrial outer membrane protein (TOM20)-positive. Ultramicroscopy revealed that PαSyn-positive granules were localized to mitochondria with degenerated inner membranes. After symptom onset, TOM20-positive granules were frequently found in ubiquitinated spheroids, where PαSyn expression was low. Axons were atrophic, but the neuronal loss was not evident in KO mice. In PLAN neurons, small PαSyn-positive inclusions with a TOM20-positive edge were frequently observed and clustered into LBs. The surfaces of most LBs were TOM20-positive in PLAN and TOM20-negative in PD brains. The high proportion of LB-bearing neurons and the preserved neuronal number in PLAN suggested long-term survival of LB-bearing neurons. Elevated expression of αSyn/PαSyn in mitochondria appears to be the early response to PLA2G6-deficiency in neurons. The strong affinity of αSyn for damaged mitochondrial membranes may promote membrane stabilization of mitochondria and neuronal survival in neurons.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan. hasumi@neurol.med.osaka-u.ac.jp.
authors.forename: Hisae
authors.initials: H
authors.lastname: Sumi-Akamaru
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Beck
authors.affiliation: Department of Medical Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan.
authors.forename: Koei
authors.initials: K
authors.lastname: Shinzawa
authors.affiliation: Division of Neuropathology, Department of Brain and Neurosciences, Tottori University Faculty of Medicine, 86 Nishi-machi, Yonago, 683-8504, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.|Institute for Medical Science of Aging, Aichi Medical University, 9 Yazakokarimata, Nagakute, 480-1195, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Riku
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, 9 Yazakokarimata, Nagakute, 480-1195, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Neurology, National Hospital Organization Toneyama National Hospital, 5-1-1 Toneyama, Toyonaka, 560-8552, Japan.
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.affiliation: Department of Medical Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan.|Research Institute Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Osaka, 537-0025, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
authors.affiliation: Department of Neurology, National Hospital Organization Toneyama National Hospital, 5-1-1 Toneyama, Toyonaka, 560-8552, Japan.
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan. hmochizuki@neurol.med.osaka-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D010300:Parkinson Disease / Q000473:pathology; D020671:Posterior Horn Cells / Q000473:pathology; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human
keywords: Lewy body; Mitochondrial membrane; PLA2G6; α-synuclein