Academic Journal
Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism
| Τίτλος: | Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism |
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| Συγγραφείς: | Chi‐Jing Choong, César Aguirre, Keita Kakuda, Goichi Beck, Hiroki Nakanishi, Yasuyoshi Kimura, Shuichi Shimma, Kei Nabekura, Makoto Hideshima, Junko Doi, Keiichi Yamaguchi, Katsuaki Nakajima, Tomoya Wadayama, Hideki Hayakawa, Kousuke Baba, Kotaro Ogawa, Toshihide Takeuchi, Shaymaa Mohamed Mohamed Badawy, Shigeo Murayama, Seiichi Nagano, Yuji Goto, Yohei Miyanoiri, Yoshitaka Nagai, Hideki Mochizuki, Kazuhiro Ikenaka |
| Πηγή: | Acta Neuropathol |
| Στοιχεία εκδότη: | Springer Science and Business Media LLC, 2023. |
| Έτος έκδοσης: | 2023 |
| Θεματικοί όροι: | Cell biology, Physiology, Parkinson's disease, Signal transduction, Biochemistry, Alpha-synuclein, Phosphatidylinositol Phosphates, Biochemistry, Genetics and Molecular Biology, Phosphatase, Health Sciences, Humans, Disease, Neurodegeneration, Phosphorylation, Biology, Internal medicine, Fibril, Neurons, a-Synuclein, Original Paper, Brain, Life Sciences, Parkinson Disease, Cell Biology, Lipids, Chemistry, Neurology, Mechanisms of Intracellular Membrane Trafficking, FOS: Biological sciences, alpha-Synuclein, Medicine, Phosphatidylinositol, Pathophysiology of Parkinson's Disease, Inositol, Lysosomal Storage Disorders in Human Health and Disease, Receptor |
| Περιγραφή: | Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson’s disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein–lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD. |
| Τύπος εγγράφου: | Article Other literature type |
| Γλώσσα: | English |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-023-02555-3 |
| DOI: | 10.60692/y0gq3-gxb82 |
| DOI: | 10.60692/yt5xc-b4p27 |
| Σύνδεσμος πρόσβασης: | https://pubmed.ncbi.nlm.nih.gov/36939875 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . |
| Αριθμός Καταχώρησης: | edsair.doi.dedup.....0fe152b5d0a194e8eb6d5afedcc674a7 |
| Βάση Δεδομένων: | OpenAIRE |
| ISSN: | 14320533 00016322 |
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| DOI: | 10.1007/s00401-023-02555-3 |