Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?
Abstract
:1. Introduction
2. Chaperone: α-Synuclein Interplay
3. Importance of the α-Synuclein Amino-terminus
4. α-Synuclein and Mitochondrial Membranes: A Fatal Relationship?
5. α-Synuclein Processing by Mitochondrial Proteins: A Facilitator of Parkinson’s Disease?
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Goedert, M.; Spillantini, M.G.; Del Tredici, K.; Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 2013, 9, 13–24. [Google Scholar] [CrossRef] [PubMed]
- Henderson, M.X.; Trojanowski, J.Q.; Lee, V.M. α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies. Neurosci. Lett. 2019, 709, 134316. [Google Scholar] [CrossRef] [PubMed]
- Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov. 2004, 3, 205–214. [Google Scholar] [CrossRef] [PubMed]
- Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-Synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013, 14, 38–48. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Mahul-Mellier, A.L.; Burtscher, J.; Maharjan, N.; Weerens, L.; Croisier, M.; Kuttler, F.; Leleu, M.; Knott, G.W.; Lashuel, H.A. The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc. Natl. Acad. Sci. USA 2020, 117, 4971–4982. [Google Scholar] [CrossRef][Green Version]
- Shahmoradian, S.H.; Lewis, A.J.; Genoud, C.; Hench, J.; Moors, T.E.; Navarro, P.P.; Castaño-Díez, D.; Schweighauser, G.; Graff-Meyer, A.; Goldie, K.N.; et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 2019, 22, 1099–1109. [Google Scholar] [CrossRef][Green Version]
- Strohäker, T.; Jung, B.C.; Liou, S.H.; Fernandez, C.O.; Riedel, D.; Becker, S.; Halliday, G.M.; Bennati, M.; Kim, W.S.; Lee, S.J.; et al. Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts. Nat. Commun. 2019, 10, 5535. [Google Scholar] [CrossRef][Green Version]
- Shahnawaz, M.; Mukherjee, A.; Pritzkow, S.; Mendez, N.; Rabadia, P.; Liu, X.; Hu, B.; Schmeichel, A.; Singer, W.; Wu, G.; et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 2020, 578, 273–277. [Google Scholar] [CrossRef]
- Boyer, D.R.; Li, B.; Sun, C.; Fan, W.; Zhou, K.; Hughes, M.P.; Sawaya, M.R.; Jiang, L.; Eisenberg, D.S. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Proc. Natl. Acad. Sci. USA 2020, 117, 3592–3602. [Google Scholar] [CrossRef]
- Boyer, D.R.; Li, B.; Sun, C.; Fan, W.; Sawaya, M.R.; Jiang, L.; Eisenberg, D.S. Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs. Nat. Struct. Mol. Biol. 2019, 26, 1044–1052. [Google Scholar] [CrossRef]
- Li, B.; Ge, P.; Murray, K.A.; Sheth, P.; Zhang, M.; Nair, G.; Sawaya, M.R.; Shin, W.S.; Boyer, D.R.; Ye, S.; et al. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat. Commun. 2018, 9, 3609. [Google Scholar] [CrossRef] [PubMed]
- Guerrero-Ferreira, R.; Taylor, N.M.; Arteni, A.A.; Kumari, P.; Mona, D.; Ringler, P.; Britschgi, M.; Lauer, M.E.; Makky, A.; Verasdonck, J.; et al. Two new polymorphic structures of human full-length α-synuclein fibrils solved by cryo-electron microscopy. eLife 2019, 8. [Google Scholar] [CrossRef] [PubMed]
- Guerrero-Ferreira, R.; Taylor, N.M.; Mona, D.; Ringler, P.; Lauer, M.E.; Riek, R.; Britschgi, M.; Stahlberg, H. Cryo-EM structure of α-synuclein fibrils. eLife 2018, 7. [Google Scholar] [CrossRef] [PubMed]
- Schweighauser, M.; Shi, Y.; Tarutani, A.; Kametani, F.; Murzin, A.G.; Ghetti, B.; Matsubara, T.; Tomita, T.; Ando, T.; Hasegawa, K.; et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 2020, 585, 464–469. [Google Scholar] [CrossRef]
- Stefanis, L. α-Synuclein in Parkinson’s Disease. Cold Spring Harb. Perspect. Med. 2012, 2. [Google Scholar] [CrossRef][Green Version]
- Alegre-Abarrategui, J.; Brimblecombe, K.R.; Roberts, R.F.; Velentza-Almpani, E.; Tilley, B.S.; Bengoa-Vergniory, N.; Proukakis, C. Selective vulnerability in α-synucleinopathies. Acta Neuropathol. 2019, 138, 681–704. [Google Scholar] [CrossRef][Green Version]
- Lau, A.; So, R.W.L.; Lau, H.H.C.; Sang, J.C.; Ruiz-Riquelme, A.; Fleck, S.C.; Stuart, E.; Menon, S.; Visanji, N.P.; Meisl, G.; et al. α-Synuclein strains target distinct brain regions and cell types. Nat. Neurosci. 2020, 23, 21–31. [Google Scholar] [CrossRef]
- Lashuel, H.A. Do Lewy bodies contain α-synuclein fibrils? and Does it matter? A brief history and critical analysis of recent reports. Neurobiol. Dis. 2020, 104876. [Google Scholar] [CrossRef]
- Gao, X.; Carroni, M.; Nussbaum-Krammer, C.; Mogk, A.; Nillegoda, N.B.; Szlachcic, A.; Guilbride, D.L.; Saibil, H.R.; Mayer, M.P.; Bukau, B. Human Hsp70 disaggregase reverses Parkinson’s-linked α-Synuclein amyloid fibrils. Mol. Cell 2015, 59, 781–793. [Google Scholar] [CrossRef][Green Version]
- Dimant, H.; Ebrahimi-Fakhari, D.; McLean, P.J. Molecular chaperones and co-chaperones in Parkinson disease. Neuroscientist 2012, 18, 589–601. [Google Scholar] [CrossRef][Green Version]
- Dedmon, M.M.; Christodoulou, J.; Wilson, M.R.; Dobson, C.M. Heat shock protein 70 inhibits α-Synuclein fibril formation via preferential binding to prefibrillar species. J. Biol. Chem. 2005, 280, 14733–14740. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Pemberton, S.; Madiona, K.; Pieri, L.; Kabani, M.; Bousset, L.; Melki, R. Hsc70 protein interaction with soluble and fibrillar α-Synuclein. J. Biol. Chem. 2011, 286, 34690–34699. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Aprile, F.A.; Arosio, P.; Fusco, G.; Chen, S.W.; Kumita, J.R.; Dhulesia, A.; Tortora, P.; Knowles, T.P.; Vendruscolo, M.; Dobson, C.M.; et al. Inhibition of α-Synuclein fibril elongation by Hsp70 is governed by a kinetic binding competition between α-synuclein species. Biochemistry 2017, 56, 1177–1180. [Google Scholar] [CrossRef] [PubMed]
- Falsone, S.F.; Kungl, A.J.; Rek, A.; Cappai, R.; Zangger, K. The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein α-Synuclein. J. Biol. Chem. 2009, 284, 31190–31199. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Xiong, R.; Zhou, W.; Siegel, D.; Kitson, R.R.; Freed, C.R.; Moody, C.J.; Ross, D. A novel Hsp90 inhibitor activates compensatory heat shock protein responses and autophagy and alleviates mutant A53T α-synuclein toxicity. Mol. Pharmacol. 2015, 88, 1045–1054. [Google Scholar] [CrossRef][Green Version]
- Du, Y.; Wang, F.; Zou, J.; Le, W.; Dong, Q.; Wang, Z.; Shen, F.; Yu, L.; Li, Y. Histone deacetylase 6 regulates cytotoxic alpha-synuclein accumulation through induction of the heat shock response. Neurobiol. Aging 2014, 35, 2316–2328. [Google Scholar] [CrossRef]
- Cox, D.; Whiten, D.R.; Brown, J.W.P.; Horrocks, M.H.; San Gil, R.; Dobson, C.M.; Klenerman, D.; van Oijen, A.M.; Ecroyd, H. The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity. J. Biol. Chem. 2018, 293, 4486–4497. [Google Scholar] [CrossRef][Green Version]
- Outeiro, T.F.; Klucken, J.; Strathearn, K.E.; Liu, F.; Nguyen, P.; Rochet, J.C.; Hyman, B.T.; McLean, P.J. Small heat shock proteins protect against α-synuclein-induced toxicity and aggregation. Biochem. Biophys. Res. Commun. 2006, 351, 631–638. [Google Scholar] [CrossRef][Green Version]
- Banerjee, P.R.; Moosa, M.M.; Deniz, A.A. Two-dimensional crowding uncovers a hidden conformation of α-Synuclein. Angew. Chem. Int. Ed. Engl. 2016, 55, 12789–12792. [Google Scholar] [CrossRef][Green Version]
- Butler, E.K.; Voigt, A.; Lutz, A.K.; Toegel, J.P.; Gerhardt, E.; Karsten, P.; Falkenburger, B.; Reinartz, A.; Winklhofer, K.F.; Schulz, J.B. The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity. PLoS Genet. 2012, 8, e1002488. [Google Scholar] [CrossRef][Green Version]
- Szego, E.M.; Dominguez-Meijide, A.; Gerhardt, E.; König, A.; Koss, D.J.; Li, W.; Pinho, R.; Fahlbusch, C.; Johnson, M.; Santos, P.; et al. Cytosolic trapping of a mitochondrial heat shock protein is an early pathological event in synucleinopathies. Cell Rep. 2019, 28, 65–77. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Horvath, I.; Blockhuys, S.; Šulskis, D.; Holgersson, S.; Kumar, R.; Burmann, B.M.; Wittung-Stafshede, P. Interaction between copper chaperone Atox1 and Parkinson’s disease protein α-Synuclein includes metal-binding sites and occurs in living cells. ACS Chem. Neurosci. 2019, 10, 4659–4668. [Google Scholar] [CrossRef] [PubMed]
- Horvath, I.; Werner, T.; Kumar, R.; Wittung-Stafshede, P. Copper chaperone blocks amyloid formation via ternary complex. Q. Rev. Biophys. 2018, 51, e6. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Burmann, B.M.; Gerez, J.A.; Matečko-Burmann, I.; Campioni, S.; Kumari, P.; Ghosh, D.; Mazur, A.; Aspholm, E.E.; Šulskis, D.; Wawrzyniuk, M.; et al. Regulation of α-synuclein by chaperones in mammalian cells. Nature 2020, 577, 127–132. [Google Scholar] [CrossRef]
- Mahul-Mellier, A.-L.; Altay, M.F.; Burtscher, J.; Maharjan, N.; Ait-Bouziad, N.; Chiki, A.; Vingill, S.; Wade-Martins, R.; Holton, J.; Strand, C.; et al. The making of a Lewy body: The role of α-synuclein post-fibrillization modifications in regulating the formation and the maturation of pathological inclusions. bioRxiv 2018. [Google Scholar] [CrossRef][Green Version]
- Doherty, C.P.A.; Ulamec, S.M.; Maya-Martinez, R.; Good, S.C.; Makepeace, J.; Khan, G.N.; van Oosten-Hawle, P.; Radford, S.E.; Brockwell, D.J. A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function. Nat. Struct. Mol. Biol. 2020, 27, 249–259. [Google Scholar] [CrossRef]
- Lorenzen, N.; Lemminger, L.; Pedersen, J.N.; Nielsen, S.B.; Otzen, D.E. The N-terminus of α-Synuclein is essential for both monomeric and oligomeric interactions with membranes. FEBS Lett. 2014, 588, 497–502. [Google Scholar] [CrossRef][Green Version]
- Stephens, A.D.; Zacharopoulou, M.; Moons, R.; Fusco, G.; Seetaloo, N.; Chiki, A.; Woodhams, P.J.; Mela, I.; Lashuel, H.A.; Phillips, J.J.; et al. Extent of N-terminus exposure of monomeric α-synuclein determines its aggregation propensity. Nat. Commun. 2020, 11, 2820. [Google Scholar] [CrossRef]
- Oueslati, A.; Schneider, B.L.; Aebischer, P.; Lashuel, H.A. Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo. Proc. Natl. Acad. Sci. USA 2013, 110, E3945–E3954. [Google Scholar] [CrossRef][Green Version]
- Ebrahimi-Fakhari, D.; McLean, P.J.; Unni, V.K. α-Synuclein’s degradation in vivo: Opening a new (cranial) window on the roles of degradation pathways in Parkinson disease. Autophagy 2012, 8, 281–283. [Google Scholar] [CrossRef][Green Version]
- Ebrahimi-Fakhari, D.; Wahlster, L.; McLean, P.J. Protein degradation pathways in Parkinson’s disease: Curse or blessing. Acta Neuropathol. 2012, 124, 153–172. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Fusco, G.; Chen, S.W.; Williamson, P.T.F.; Cascella, R.; Perni, M.; Jarvis, J.A.; Cecchi, C.; Vendruscolo, M.; Chiti, F.; Cremades, N.; et al. Structural basis of membrane disruption and cellular toxicity by α-Synuclein oligomers. Science 2017, 358, 1440–1443. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Giehm, L.; Svergun, D.I.; Otzen, D.E.; Vestergaard, B. Low-resolution structure of a vesicle disrupting α-Synuclein oligomer that accumulates during fibrillation. Proc. Natl. Acad. Sci. USA 2011, 108, 3246–3251. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Fusco, G.; Pape, T.; Stephens, A.D.; Mahou, P.; Costa, A.R.; Kaminski, C.F.; Kaminski Schierle, G.S.; Vendruscolo, M.; Veglia, G.; Dobson, C.M.; et al. Structural basis of synaptic vesicle assembly promoted by α-Synuclein. Nat. Commun. 2016, 7, 12563. [Google Scholar] [CrossRef][Green Version]
- Lautenschläger, J.; Wagner-Valladolid, S.; Stephens, A.D.; Fernandez-Villegas, A.; Hockings, C.; Mishra, A.; Manton, J.D.; Fantham, M.J.; Lu, M.; Rees, E.J.; et al. Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid beta 1-42 pathologies. J. Biol. Chem. 2020, 295, 10138–10152. [Google Scholar] [CrossRef]
- Karagöz, G.E.; Duarte, A.M.; Akoury, E.; Ippel, H.; Biernat, J.; Moran Luengo, T.; Radli, M.; Didenko, T.; Nordhues, B.A.; Veprintsev, D.B.; et al. Hsp90-Tau complex reveals molecular basis for specificity in chaperone action. Cell 2014, 156, 963–974. [Google Scholar] [CrossRef][Green Version]
- Diao, J.; Burre, J.; Vivona, S.; Cipriano, D.J.; Sharma, M.; Kyoung, M.; Südhof, T.C.; Brunger, A.T. Native α-Synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. eLife 2013, 2, e00592. [Google Scholar] [CrossRef]
- Fusco, G.; De Simone, A.; Arosio, P.; Vendruscolo, M.; Veglia, G.; Dobson, C.M. Structural ensembles of membrane-bound α-synuclein reveal the molecular determinants of synaptic vesicle affinity. Sci. Rep. 2016, 6, 27125. [Google Scholar] [CrossRef][Green Version]
- Cartelli, D.; Aliverti, A.; Barbiroli, A.; Santambrogio, C.; Ragg, E.M.; Casagrande, F.V.; Cantele, F.; Beltramone, S.; Marangon, J.; De Gregorio, C.; et al. α-Synuclein is a novel microtubule dynamase. Sci. Rep. 2016, 6, 33289. [Google Scholar] [CrossRef][Green Version]
- Carnwath, T.; Mohammed, R.; Tsiang, D. The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease. Neuropsychiatr. Dis. Treat. 2018, 14, 1685–1695. [Google Scholar] [CrossRef][Green Version]
- Chen, L.; Jin, J.; Davis, J.; Zhou, Y.; Wang, Y.; Liu, J.; Lockhart, P.J.; Zhang, J. Oligomeric α-Synuclein inhibits tubulin polymerization. Biochem. Biophys. Res. Commun. 2007, 356, 548–553. [Google Scholar] [CrossRef] [PubMed]
- Alim, M.A.; Ma, Q.L.; Takeda, K.; Aizawa, T.; Matsubara, M.; Nakamura, M.; Asada, A.; Saito, T.; Kaji, H.; Yoshii, M.; et al. Demonstration of a role for α-Synuclein as a functional microtubule-associated protein. J. Alzheimers Dis. 2004, 6, 435–442. [Google Scholar] [CrossRef] [PubMed]
- Joachimiak, L.A.; Walzthoeni, T.; Liu, C.W.; Aebersold, R.; Frydman, J. The structural basis of substrate recognition by the eukaryotic chaperonin TRiC/CCT. Cell 2014, 159, 1042–1055. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ulmer, T.S.; Bax, A.; Cole, N.B.; Nussbaum, R.L. Structure and dynamics of micelle-bound human α-synuclein. J. Biol. Chem. 2005, 280, 9595–9603. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Fusco, G.; De Simone, A.; Gopinath, T.; Vostrikov, V.; Vendruscolo, M.; Dobson, C.M.; Veglia, G. Direct observation of the three regions in α-Synuclein that determine its membrane-bound behaviour. Nat. Commun. 2014, 5, 3827. [Google Scholar] [CrossRef] [PubMed]
- Theillet, F.X.; Binolfi, A.; Bekei, B.; Martorana, A.; Rose, H.M.; Stuiver, M.; Verzini, S.; Lorenz, D.; van Rossum, M.; Goldfarb, D.; et al. Structural disorder of monomeric α-Synuclein persists in mammalian cells. Nature 2016, 530, 45–50. [Google Scholar] [CrossRef][Green Version]
- Matečko-Burmann, I.; Burmann, B.M. Recording in-cell NMR-spectra in living mammalian cells. Methods Mol. Biol. 2020, 2141, 857–871. [Google Scholar] [CrossRef]
- Maltsev, A.S.; Ying, J.; Bax, A. Impact of N-terminal acetylation of α-Synuclein on its random coil and lipid binding properties. Biochemistry 2012, 51, 5004–5013. [Google Scholar] [CrossRef]
- Schneider, M.M.; Gautam, S.; Herling, T.W.; Andrzejewska, E.; Krainer, G.; Miller, A.M.; Peter, Q.A.E.; Ruggeri, F.S.; Vendruscolo, M.; Bracher, A.; et al. The Hsc70 Disaggregation Machinery Removes Monomer Units Directly from α-Synuclein Fibril Ends. bioRxiv 2020. [Google Scholar] [CrossRef]
- Bartels, T.; Choi, J.G.; Selkoe, D.J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477, 107–110. [Google Scholar] [CrossRef][Green Version]
- Kang, L.; Moriarty, G.M.; Woods, L.A.; Ashcroft, A.E.; Radford, S.E.; Baum, J. N-terminal acetylation of α-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer. Protein Sci. 2012, 21, 911–917. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tuttle, M.D.; Comellas, G.; Nieuwkoop, A.J.; Covell, D.J.; Berthold, D.A.; Kloepper, K.D.; Courtney, J.M.; Kim, J.K.; Barclay, A.M.; Kendall, A.; et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat. Struct. Mol. Biol. 2016, 23, 409–415. [Google Scholar] [CrossRef] [PubMed]
- Giasson, B.I.; Murray, I.V.; Trojanowski, J.Q.; Lee, V.M. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J. Biol. Chem. 2001, 276, 2380–2386. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Stephens, A.D.; Zacharopoulou, M.; Kaminski Schierle, G.S. The cellular environment affects monomeric α-Synuclein structure. Trends Biochem. Sci. 2019, 44, 453–466. [Google Scholar] [CrossRef]
- Binolfi, A.; Rasia, R.M.; Bertoncini, C.W.; Ceolin, M.; Zweckstetter, M.; Griesinger, C.; Jovin, T.M.; Fernandez, C.O. Interaction of α-synuclein with divalent metal ions reveals key differences: A link between structure, binding specificity and fibrillation enhancement. J. Am. Chem. Soc. 2006, 128, 9893–9901. [Google Scholar] [CrossRef]
- Lautenschläger, J.; Stephens, A.D.; Fusco, G.; Strohl, F.; Curry, N.; Zacharopoulou, M.; Michel, C.H.; Laine, R.; Nespovitaya, N.; Fantham, M.; et al. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat. Commun. 2018, 9, 712. [Google Scholar] [CrossRef][Green Version]
- Wang, W.; Nguyen, L.T.T.; Burlak, C.; Chegini, F.; Guo, F.; Chataway, T.; Ju, S.L.; Fisher, O.S.; Miller, D.W.; Datta, D.; et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl. Acad. Sci. USA 2016, 113, 9587–9592. [Google Scholar] [CrossRef][Green Version]
- Surmeier, D.J.; Guzman, J.N.; Sanchez-Padilla, J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium 2010, 47, 175–182. [Google Scholar] [CrossRef][Green Version]
- Nakamura, K. α-Synuclein and mitochondria: Partners in crime? Neurotherapeutics 2013, 10, 391–399. [Google Scholar] [CrossRef][Green Version]
- Rideout, H.J.; Dietrich, P.; Savalle, M.; Dauer, W.T.; Stefanis, L. Regulation of α-synuclein by bFGF in cultured ventral midbrain dopaminergic neurons. J. Neurochem. 2003, 84, 803–813. [Google Scholar] [CrossRef]
- Li, W.W.; Yang, R.; Guo, J.C.; Ren, H.M.; Zha, X.L.; Cheng, J.S.; Cai, D.F. Localization of α-synuclein to mitochondria within midbrain of mice. Neuroreport 2007, 18, 1543–1546. [Google Scholar] [CrossRef] [PubMed]
- Martin, L.J.; Pan, Y.; Price, A.C.; Sterling, W.; Copeland, N.G.; Jenkins, N.A.; Price, D.L.; Lee, M.K. Parkinson’s disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 2006, 26, 41–50. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Burre, J. The synaptic function of α-synuclein. J. Parkinson’s Dis. 2015, 5, 699–713. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Cole, N.B.; Dieuliis, D.; Leo, P.; Mitchell, D.C.; Nussbaum, R.L. Mitochondrial translocation of α-synuclein is promoted by intracellular acidification. Exp. Cell. Res. 2008, 314, 2076–2089. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Cuervo, A.M.; Stefanis, L.; Fredenburg, R.; Lansbury, P.T.; Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 2004, 305, 1292–1295. [Google Scholar] [CrossRef] [PubMed]
- Kamp, F.; Exner, N.; Lutz, A.K.; Wender, N.; Hegermann, J.; Brunner, B.; Nuscher, B.; Bartels, T.; Giese, A.; Beyer, K.; et al. Inhibition of mitochondrial fusion by α-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 2010, 29, 3571–3589. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Nakamura, K.; Nemani, V.M.; Azarbal, F.; Skibinski, G.; Levy, J.M.; Egami, K.; Munishkina, L.; Zhang, J.; Gardner, B.; Wakabayashi, J.; et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein. J. Biol. Chem. 2011, 286, 20710–20726. [Google Scholar] [CrossRef][Green Version]
- Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial import and accumulation of α-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 2008, 283, 9089–9100. [Google Scholar] [CrossRef][Green Version]
- Fusco, G.; Sanz-Hernandez, M.; De Simone, A. Order and disorder in the physiological membrane binding of α-Synuclein. Curr. Opin. Struct. Biol. 2018, 48, 49–57. [Google Scholar] [CrossRef]
- Ludtmann, M.H.; Angelova, P.R.; Ninkina, N.N.; Gandhi, S.; Buchman, V.L.; Abramov, A.Y. Monomeric α-Synuclein exerts a physiological role on brain ATP synthase. J. Neurosci. 2016, 36, 10510–10521. [Google Scholar] [CrossRef]
- Dettmer, U.; Newman, A.J.; Soldner, F.; Luth, E.S.; Kim, N.C.; von Saucken, V.E.; Sanderson, J.B.; Jaenisch, R.; Bartels, T.; Selkoe, D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 2015, 6, 7314. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dettmer, U.; Newman, A.J.; von Saucken, V.E.; Bartels, T.; Selkoe, D. KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity. Proc. Natl. Acad. Sci. USA 2015, 112, 9596–9601. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dettmer, U.; Selkoe, D.; Bartels, T. New insights into cellular α-synuclein homeostasis in health and disease. Curr. Opin. Neurobiol. 2016, 36, 15–22. [Google Scholar] [CrossRef] [PubMed]
- Hashimoto, M.; Hsu, L.J.; Sisk, A.; Xia, Y.; Takeda, A.; Sundsmo, M.; Masliah, E. Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease. Brain Res. 1998, 799, 301–306. [Google Scholar] [CrossRef]
- Hashimoto, M.; Hsu, L.J.; Xia, Y.; Takeda, A.; Sisk, A.; Sundsmo, M.; Masliah, E. Oxidative stress induces amyloid-like aggregate formation of NACP/α-synuclein in vitro. Neuroreport 1999, 10, 717–721. [Google Scholar] [CrossRef] [PubMed]
- Mahul-Mellier, A.L.; Fauvet, B.; Gysbers, A.; Dikiy, I.; Oueslati, A.; Georgeon, S.; Lamontanara, A.J.; Bisquertt, A.; Eliezer, D.; Masliah, E.; et al. c-Abl phosphorylates α-Synuclein and regulates its degradation: Implication for α-Synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum. Mol. Genet. 2014, 23, 2858–2879. [Google Scholar] [CrossRef][Green Version]
- Dikiy, I.; Fauvet, B.; Jovicic, A.; Mahul-Mellier, A.L.; Desobry, C.; El-Turk, F.; Gitler, A.D.; Lashuel, H.A.; Eliezer, D. Semisynthetic and in vitro phosphorylation of α-Synuclein at Y39 promotes functional partly helical membrane-bound states resembling those induced by PD mutations. ACS Chem. Biol. 2016, 11, 2428–2437. [Google Scholar] [CrossRef][Green Version]
- Tenreiro, S.; Eckermann, K.; Outeiro, T.F. Protein phosphorylation in neurodegeneration: Friend or foe? Front. Mol. Neurosci. 2014, 7, 42. [Google Scholar] [CrossRef][Green Version]
- Binolfi, A.; Limatola, A.; Verzini, S.; Kosten, J.; Theillet, F.X.; Rose, H.M.; Bekei, B.; Stuiver, M.; van Rossum, M.; Selenko, P. Intracellular repair of oxidation-damaged α-Synuclein fails to target C-terminal modification sites. Nat. Commun. 2016, 7, 10251. [Google Scholar] [CrossRef][Green Version]
- Maltsev, A.S.; Chen, J.; Levine, R.L.; Bax, A. Site-specific interaction between α-Synuclein and membranes probed by NMR-observed methionine oxidation rates. J. Am. Chem. Soc. 2013, 135, 2943–2946. [Google Scholar] [CrossRef]
- Vicente Miranda, H.; Szego, E.M.; Oliveira, L.M.A.; Breda, C.; Darendelioglu, E.; de Oliveira, R.M.; Ferreira, D.G.; Gomes, M.A.; Rott, R.; Oliveira, M.; et al. Glycation potentiates α-Synuclein-associated neurodegeneration in synucleinopathies. Brain 2017, 140, 1399–1419. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Vicente Miranda, H.; El-Agnaf, O.M.; Outeiro, T.F. Glycation in Parkinson’s disease and Alzheimer’s disease. Mov. Disord. 2016, 31, 782–790. [Google Scholar] [CrossRef] [PubMed]
- Krumova, P.; Meulmeester, E.; Garrido, M.; Tirard, M.; Hsiao, H.H.; Bossis, G.; Urlaub, H.; Zweckstetter, M.; Kugler, S.; Melchior, F.; et al. Sumoylation inhibits α-Synuclein aggregation and toxicity. J. Cell Biol. 2011, 194, 49–60. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dorval, V.; Fraser, P.E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and α-Synuclein. J. Biol. Chem. 2006, 281, 9919–9924. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Snead, D.; Eliezer, D. α-Synuclein function and dysfunction on cellular membranes. Exp. Neurobiol. 2014, 23, 292–313. [Google Scholar] [CrossRef][Green Version]
- Winner, B.; Jappelli, R.; Maji, S.K.; Desplats, P.A.; Boyer, L.; Aigner, S.; Hetzer, C.; Loher, T.; Vilar, M.; Campioni, S.; et al. In vivo demonstration that α-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. USA 2011, 108, 4194–4199. [Google Scholar] [CrossRef][Green Version]
- Lee, H.J.; Choi, C.; Lee, S.J. Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J. Biol. Chem. 2002, 277, 671–678. [Google Scholar] [CrossRef][Green Version]
- Nakamura, K.; Nemani, V.M.; Wallender, E.K.; Kaehlcke, K.; Ott, M.; Edwards, R.H. Optical reporters for the conformation of α-synuclein reveal a specific interaction with mitochondria. J. Neurosci. 2008, 28, 12305–12317. [Google Scholar] [CrossRef]
- Dudek, J. Role of Cardiolipin in Mitochondrial Signaling Pathways. Front. Cell. Dev. Biol. 2017, 5, 90. [Google Scholar] [CrossRef][Green Version]
- Zigoneanu, I.G.; Yang, Y.J.; Krois, A.S.; Haque, E.; Pielak, G.J. Interaction of α-synuclein with vesicles that mimic mitochondrial membranes. Biochim. Biophys. Acta 2012, 1818, 512–519. [Google Scholar] [CrossRef][Green Version]
- Necula, M.; Chirita, C.N.; Kuret, J. Rapid anionic micelle-mediated α-synuclein fibrillization in vitro. J. Biol. Chem. 2003, 278, 46674–46680. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Luth, E.S.; Stavrovskaya, I.G.; Bartels, T.; Kristal, B.S.; Selkoe, D.J. Soluble, prefibrillar α-Synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 2014, 289, 21490–21507. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Angelova, P.R.; Ludtmann, M.H.; Horrocks, M.H.; Negoda, A.; Cremades, N.; Klenerman, D.; Dobson, C.M.; Wood, N.W.; Pavlov, E.V.; Gandhi, S.; et al. Ca2+ is a key factor in α-Synuclein-induced neurotoxicity. J. Cell Sci. 2016, 129, 1792–1801. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Colbeau, A.; Nachbaur, J.; Vignais, P.M. Enzymic characterization and lipid composition of rat liver subcellular membranes. Biochim. Biophys. Acta 1971, 249, 462–492. [Google Scholar] [CrossRef]
- Klingenberg, M. Cardiolipin and mitochondrial carriers. Biochim. Biophys. Acta 2009, 1788, 2048–2058. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Chu, C.T.; Ji, J.; Dagda, R.K.; Jiang, J.F.; Tyurina, Y.Y.; Kapralov, A.A.; Tyurin, V.A.; Yanamala, N.; Shrivastava, I.H.; Mohammadyani, D.; et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat. Cell. Biol. 2013, 15, 1197–1205. [Google Scholar] [CrossRef][Green Version]
- Pickles, S.; Vigie, P.; Youle, R.J. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 2018, 28, R170–R185. [Google Scholar] [CrossRef]
- Youle, R.J.; Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 2011, 12, 9–14. [Google Scholar] [CrossRef]
- Dernie, F. Mitophagy in Parkinson’s disease: From pathogenesis to treatment target. Neurochem. Int. 2020, 138, 104756. [Google Scholar] [CrossRef]
- Vives-Bauza, C.; Przedborski, S. Mitophagy: The latest problem for Parkinson’s disease. Trends Mol. Med. 2011, 17, 158–165. [Google Scholar] [CrossRef]
- Dantuma, N.P.; Bott, L.C. The ubiquitin-proteasome system in neurodegenerative diseases: Precipitating factor, yet part of the solution. Front. Mol. Neurosci. 2014, 7, 70. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Mallucci, G.R.; Klenerman, D.; Rubinsztein, D.C. Developing Therapies for Neurodegenerative Disorders: Insights from Protein Aggregation and Cellular Stress Responses. Annu. Rev. Cell. Dev. Biol. 2020, 36, 165–189. [Google Scholar] [CrossRef] [PubMed]
- Verhoef, L.G.; Lindsten, K.; Masucci, M.G.; Dantuma, N.P. Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum. Mol. Genet. 2002, 11, 2689–2700. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hara, T.; Nakamura, K.; Matsui, M.; Yamamoto, A.; Nakahara, Y.; Suzuki-Migishima, R.; Yokoyama, M.; Mishima, K.; Saito, I.; Okano, H.; et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441, 885–889. [Google Scholar] [CrossRef]
- Winslow, A.R.; Chen, C.W.; Corrochano, S.; Acevedo-Arozena, A.; Gordon, D.E.; Peden, A.A.; Lichtenberg, M.; Menzies, F.M.; Ravikumar, B.; Imarisio, S.; et al. α-Synuclein impairs macroautophagy: Implications for Parkinson’s disease. J. Cell Biol. 2010, 190, 1023–1037. [Google Scholar] [CrossRef][Green Version]
- Kourtis, N.; Tavernarakis, N. Cellular stress response pathways and ageing: Intricate molecular relationships. EMBO J. 2011, 30, 2520–2531. [Google Scholar] [CrossRef][Green Version]
- Ben-Zvi, A.; Miller, E.A.; Morimoto, R.I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl. Acad. Sci. USA 2009, 106, 14914–14919. [Google Scholar] [CrossRef][Green Version]
- Sala, G.; Stefanoni, G.; Arosio, A.; Riva, C.; Melchionda, L.; Saracchi, E.; Fermi, S.; Brighina, L.; Ferrarese, C. Reduced expression of the chaperone-mediated autophagy carrier Hsc70 protein in lymphomonocytes of patients with Parkinson’s disease. Brain Res. 2014, 1546, 46–52. [Google Scholar] [CrossRef]
- Kaushik, S.; Cuervo, A.M. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 2018, 19, 365–381. [Google Scholar] [CrossRef]
- Middleton, E.R.; Rhoades, E. Effects of curvature and composition on α-synuclein binding to lipid vesicles. Biophys. J. 2010, 99, 2279–2288. [Google Scholar] [CrossRef][Green Version]
- Galvagnion, C.; Buell, A.K.; Meisl, G.; Michaels, T.C.; Vendruscolo, M.; Knowles, T.P.; Dobson, C.M. Lipid vesicles trigger α-Synuclein aggregation by stimulating primary nucleation. Nat. Chem. Biol. 2015, 11, 229–234. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Zeczycki, T.N.; Whelan, J.; Hayden, W.T.; Brown, D.A.; Shaikh, S.R. Increasing levels of cardiolipin differentially influence packing of phospholipids found in the mitochondrial inner membrane. Biochem. Biophys. Res. Commun. 2014, 450, 366–371. [Google Scholar] [CrossRef] [PubMed]
- Vamvaca, K.; Lansbury, P.T., Jr.; Stefanis, L. N-terminal deletion does not affect α-synuclein membrane binding, self-association and toxicity in human neuroblastoma cells, unlike yeast. J. Neurochem. 2011, 119, 389–397. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Bhattacharyya, D.; Mohite, G.M.; Krishnamoorthy, J.; Gayen, N.; Mehra, S.; Navalkar, A.; Kotler, S.A.; Ratha, B.N.; Ghosh, A.; Kumar, R.; et al. Lipopolysaccharide from gut microbiota modulates α-synuclein aggregation and alters its biological function. ACS Chem. Neurosci. 2019, 10, 2229–2236. [Google Scholar] [CrossRef]
- Gallop, J.L.; Jao, C.C.; Kent, H.M.; Butler, P.J.; Evans, P.R.; Langen, R.; McMahon, H.T. Mechanism of endophilin N-BAR domain-mediated membrane curvature. EMBO J. 2006, 25, 2898–2910. [Google Scholar] [CrossRef][Green Version]
- Davidson, W.S.; Jonas, A.; Clayton, D.F.; George, J.M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 1998, 273, 9443–9449. [Google Scholar] [CrossRef][Green Version]
- Endo, T.; Yamano, K. Transport of proteins across or into the mitochondrial outer membrane. Biochim. Biophys. Acta 2010, 1803, 706–714. [Google Scholar] [CrossRef][Green Version]
- Neupert, W. A perspective on transport of proteins into mitochondria: A myriad of open questions. J. Mol. Biol. 2015, 427, 1135–1158. [Google Scholar] [CrossRef]
- Pfanner, N.; Warscheid, B.; Wiedemann, N. Mitochondrial proteins: From biogenesis to functional networks. Nat. Rev. Mol. Cell Biol. 2019, 20, 267–284. [Google Scholar] [CrossRef]
- Hiller, S.; Garces, R.G.; Malia, T.J.; Orekhov, V.Y.; Colombini, M.; Wagner, G. Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science 2008, 321, 1206–1210. [Google Scholar] [CrossRef][Green Version]
- Rostovtseva, T.K.; Gurnev, P.A.; Protchenko, O.; Hoogerheide, D.P.; Yap, T.L.; Philpott, C.C.; Lee, J.C.; Bezrukov, S.M. α-Synuclein shows high affinity interaction with Voltage-dependent Anion Channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J. Biol. Chem. 2015, 290, 18467–18477. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ludtmann, M.H.R.; Angelova, P.R.; Horrocks, M.H.; Choi, M.L.; Rodrigues, M.; Baev, A.Y.; Berezhnov, A.V.; Yao, Z.; Little, D.; Banushi, B.; et al. α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nat. Commun. 2018, 9, 2293. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tripathi, T.; Chattopadhyay, K. Interaction of α-Synuclein with ATP synthase: Switching role from physiological to pathological. ACS Chem. Neurosci. 2019, 10, 16–17. [Google Scholar] [CrossRef] [PubMed]
- Guardia-Laguarta, C.; Area-Gomez, E.; Schon, E.A.; Przedborski, S. Novel subcellular localization for α-synuclein: Possible functional consequences. Front. Neuroanat. 2015, 9, 17. [Google Scholar] [CrossRef][Green Version]
- Di Maio, R.; Barrett, P.J.; Hoffman, E.K.; Barrett, C.W.; Zharikov, A.; Borah, A.; Hu, X.; McCoy, J.; Chu, C.T.; Burton, E.A.; et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Transl. Med. 2016, 8, 342ra378. [Google Scholar] [CrossRef][Green Version]
- Esteves, A.R.; Lu, J.; Rodova, M.; Onyango, I.; Lezi, E.; Dubinsky, R.; Lyons, K.E.; Pahwa, R.; Burns, J.M.; Cardoso, S.M.; et al. Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson’s subject mitochondrial transfer. J. Neurochem. 2010, 113, 674–682. [Google Scholar] [CrossRef]
- Puspita, L.; Chung, S.Y.; Shim, J.W. Oxidative stress and cellular pathologies in Parkinson’s disease. Mol. Brain 2017, 10, 53. [Google Scholar] [CrossRef][Green Version]
- Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002, 82, 47–95. [Google Scholar] [CrossRef]
- Krokan, H.E.; Standal, R.; Slupphaug, G. DNA glycosylases in the base excision repair of DNA. Biochem. J. 1997, 325, 1–16. [Google Scholar] [CrossRef]
- Park, J.H.; Burgess, J.D.; Faroqi, A.H.; DeMeo, N.N.; Fiesel, F.C.; Springer, W.; Delenclos, M.; McLean, P.J. α-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway. Mol. Neurodegener. 2020, 15, 5. [Google Scholar] [CrossRef][Green Version]
- Bush, A.I. Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol. Aging 2002, 23, 1031–1038. [Google Scholar] [CrossRef]
- Vranova, E.; Inze, D.; Van Breusegem, F. Signal transduction during oxidative stress. J. Exp. Bot. 2002, 53, 1227–1236. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Paxinou, E.; Chen, Q.; Weisse, M.; Giasson, B.I.; Norris, E.H.; Rueter, S.M.; Trojanowski, J.Q.; Lee, V.M.; Ischiropoulos, H. Induction of α-synuclein aggregation by intracellular nitrative insult. J. Neurosci. 2001, 21, 8053–8061. [Google Scholar] [CrossRef] [PubMed]
- Ischiropoulos, H.; Beckman, J.S. Oxidative stress and nitration in neurodegeneration: Cause, effect, or association? J. Clin. Investig. 2003, 111, 163–169. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Verzini, S.; Shah, M.; Theillet, F.-X.; Belsom, A.; Bieschke, J.; Wanker, E.E.; Rappsilber, J.; Binolfi, A.; Selenko, P. Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics. J. Mol. Biol. 2020, in press. [Google Scholar] [CrossRef]
- Souza, J.M.; Giasson, B.I.; Chen, Q.; Lee, V.M.; Ischiropoulos, H. Dityrosine cross-linking promotes formation of stable α-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 2000, 275, 18344–18349. [Google Scholar] [CrossRef][Green Version]
- Bayir, H.; Kapralov, A.A.; Jiang, J.; Huang, Z.; Tyurina, Y.Y.; Tyurin, V.A.; Zhao, Q.; Belikova, N.A.; Vlasova, I.I.; Maeda, A.; et al. Peroxidase mechanism of lipid-dependent cross-linking of synuclein with cytochrome C: Protection against apoptosis versus delayed oxidative stress in Parkinson disease. J. Biol. Chem. 2009, 284, 15951–15969. [Google Scholar] [CrossRef][Green Version]
- Lee, H.J.; Shin, S.Y.; Choi, C.; Lee, Y.H.; Lee, S.J. Formation and removal of α-synuclein aggregates in cells exposed to mitochondrial inhibitors. J. Biol. Chem. 2002, 277, 5411–5417. [Google Scholar] [CrossRef][Green Version]
- Nieto, M.; Gil-Bea, F.J.; Dalfo, E.; Cuadrado, M.; Cabodevilla, F.; Sanchez, B.; Catena, S.; Sesma, T.; Ribe, E.; Ferrer, I.; et al. Increased sensitivity to MPTP in human α-synuclein A30P transgenic mice. Neurobiol. Aging 2006, 27, 848–856. [Google Scholar] [CrossRef]
- Piltonen, M.; Savolainen, M.; Patrikainen, S.; Baekelandt, V.; Myohanen, T.T.; Mannisto, P.T. Comparison of motor performance, brain biochemistry and histology of two A30P α-synuclein transgenic mouse strains. Neuroscience 2013, 231, 157–168. [Google Scholar] [CrossRef]
- Quiros, P.M.; Langer, T.; Lopez-Otin, C. New roles for mitochondrial proteases in health, ageing and disease. Nat. Rev. Mol. Cell Biol. 2015, 16, 345–359. [Google Scholar] [CrossRef] [PubMed]
- Patron, M.; Sprenger, H.G.; Langer, T. m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. Cell Res. 2018, 28, 296–306. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Franco-Iborra, S.; Vila, M.; Perier, C. Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson’s Disease and Huntington’s Disease. Front. Neurosci. 2018, 12, 342. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Martinelli, P.; Rugarli, E.I. Emerging roles of mitochondrial proteases in neurodegeneration. Biochim. Biophys. Acta 2010, 1797, 1–10. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Bolliger, L.; Junne, T.; Schatz, G.; Lithgow, T. Acidic receptor domains on both sides of the outer membrane mediate translocation of precursor proteins into yeast mitochondria. EMBO J. 1995, 14, 6318–6326. [Google Scholar] [CrossRef] [PubMed]
- Dolgacheva, L.P.; Berezhnov, A.V.; Fedotova, E.I.; Zinchenko, V.P.; Abramov, A.Y. Role of DJ-1 in the mechanism of pathogenesis of Parkinson’s disease. J. Bioenerg. Biomembr. 2019, 51, 175–188. [Google Scholar] [CrossRef][Green Version]
- Zondler, L.; Miller-Fleming, L.; Repici, M.; Goncalves, S.; Tenreiro, S.; Rosado-Ramos, R.; Betzer, C.; Straatman, K.R.; Jensen, P.H.; Giorgini, F.; et al. DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson’s disease. Cell. Death Dis. 2014, 5, e1350. [Google Scholar] [CrossRef][Green Version]
- Malgieri, G.; Eliezer, D. Structural effects of Parkinson’s disease linked DJ-1 mutations. Protein Sci. 2008, 17, 855–868. [Google Scholar] [CrossRef][Green Version]
- Repici, M.; Straatman, K.R.; Balduccio, N.; Enguita, F.J.; Outeiro, T.F.; Giorgini, F. Parkinson’s disease-associated mutations in DJ-1 modulate its dimerization in living cells. J. Mol. Med. 2013, 91, 599–611. [Google Scholar] [CrossRef][Green Version]
- Moore, D.J.; Zhang, L.; Troncoso, J.; Lee, M.K.; Hattori, N.; Mizuno, Y.; Dawson, T.M.; Dawson, V.L. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. 2005, 14, 71–84. [Google Scholar] [CrossRef][Green Version]
- Shendelman, S.; Jonason, A.; Martinat, C.; Leete, T.; Abeliovich, A. DJ-1 is a redox-dependent molecular chaperone that inhibits α-synuclein aggregate formation. PLoS Biol. 2004, 2, e362. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Kumar, R.; Kumar, S.; Hanpude, P.; Singh, A.K.; Johari, T.; Majumder, S.; Maiti, T.K. Partially oxidized DJ-1 inhibits α-synuclein nucleation and remodels mature α-synuclein fibrils in vitro. Commun. Biol. 2019, 2, 395. [Google Scholar] [CrossRef] [PubMed]
- Jin, J.; Meredith, G.E.; Chen, L.; Zhou, Y.; Xu, J.; Shie, F.S.; Lockhart, P.; Zhang, J. Quantitative proteomic analysis of mitochondrial proteins: Relevance to Lewy body formation and Parkinson’s disease. Brain Res. Mol. Brain Res. 2005, 134, 119–138. [Google Scholar] [CrossRef] [PubMed]
- Xu, C.Y.; Kang, W.Y.; Chen, Y.M.; Jiang, T.F.; Zhang, J.; Zhang, L.N.; Ding, J.Q.; Liu, J.; Chen, S.D. DJ-1 Inhibits α-synuclein aggregation by regulating chaperone-mediated autophagy. Front. Aging Neurosci. 2017, 9, 308. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hegde, R.; Srinivasula, S.M.; Zhang, Z.; Wassell, R.; Mukattash, R.; Cilenti, L.; DuBois, G.; Lazebnik, Y.; Zervos, A.S.; Fernandes-Alnemri, T.; et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 2002, 277, 432–438. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Li, W.; Srinivasula, S.M.; Chai, J.; Li, P.; Wu, J.W.; Zhang, Z.; Alnemri, E.S.; Shi, Y. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat. Struct. Biol. 2002, 9, 436–441. [Google Scholar] [CrossRef]
- Zhang, Y.; Appleton, B.A.; Wu, P.; Wiesmann, C.; Sidhu, S.S. Structural and functional analysis of the ligand specificity of the HtrA2/Omi PDZ domain. Protein Sci. 2007, 16, 1738–1750. [Google Scholar] [CrossRef][Green Version]
- Jones, J.M.; Datta, P.; Srinivasula, S.M.; Ji, W.; Gupta, S.; Zhang, Z.; Davies, E.; Hajnoczky, G.; Saunders, T.L.; Van Keuren, M.L.; et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 2003, 425, 721–727. [Google Scholar] [CrossRef][Green Version]
- Unal Gulsuner, H.; Gulsuner, S.; Mercan, F.N.; Onat, O.E.; Walsh, T.; Shahin, H.; Lee, M.K.; Dogu, O.; Kansu, T.; Topaloglu, H.; et al. Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease. Proc. Natl. Acad. Sci. USA 2014, 111, 18285–18290. [Google Scholar] [CrossRef][Green Version]
- Lin, C.H.; Chen, M.L.; Chen, G.S.; Tai, C.H.; Wu, R.M. Novel variant Pro143Ala in HTRA2 contributes to Parkinson’s disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria. Hum. Genet. 2011, 130, 817–827. [Google Scholar] [CrossRef][Green Version]
- Kawamoto, Y.; Kobayashi, Y.; Suzuki, Y.; Inoue, H.; Tomimoto, H.; Akiguchi, I.; Budka, H.; Martins, L.M.; Downward, J.; Takahashi, R. Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with α-synucleinopathies. J. Neuropathol. Exp. Neurol. 2008, 67, 984–993. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Strauss, K.M.; Martins, L.M.; Plun-Favreau, H.; Marx, F.P.; Kautzmann, S.; Berg, D.; Gasser, T.; Wszolek, Z.; Muller, T.; Bornemann, A.; et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum. Mol. Genet. 2005, 14, 2099–2111. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Plun-Favreau, H.; Gandhi, S.; Wood-Kaczmar, A.; Deas, E.; Yao, Z.; Wood, N.W. What have PINK1 and HtrA2 genes told us about the role of mitochondria in Parkinson’s disease? Ann. N. Y. Acad. Sci. 2008, 1147, 30–36. [Google Scholar] [CrossRef] [PubMed]
- Plun-Favreau, H.; Klupsch, K.; Moisoi, N.; Gandhi, S.; Kjaer, S.; Frith, D.; Harvey, K.; Deas, E.; Harvey, R.J.; McDonald, N.; et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat. Cell. Biol. 2007, 9, 1243–1252. [Google Scholar] [CrossRef]
- Fitzgerald, J.C.; Camprubi, M.D.; Dunn, L.; Wu, H.C.; Ip, N.Y.; Kruger, R.; Martins, L.M.; Wood, N.W.; Plun-Favreau, H. Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function. Cell Death Differ. 2012, 19, 257–266. [Google Scholar] [CrossRef][Green Version]
- Hu, D.; Sun, X.; Liao, X.; Zhang, X.; Zarabi, S.; Schimmer, A.; Hong, Y.; Ford, C.; Luo, Y.; Qi, X. α-Synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta Neuropathol. 2019, 137, 939–960. [Google Scholar] [CrossRef][Green Version]
- Sauer, R.T.; Baker, T.A. AAA+ proteases: ATP-fueled machines of protein destruction. Annu. Rev. Biochem. 2011, 80, 587–612. [Google Scholar] [CrossRef]
- Conway, K.A.; Harper, J.D.; Lansbury, P.T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nat. Med. 1998, 4, 1318–1320. [Google Scholar] [CrossRef]
- Liu, C.W.; Giasson, B.I.; Lewis, K.A.; Lee, V.M.; Demartino, G.N.; Thomas, P.J. A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation: Implications for pathogenesis of Parkinson disease. J. Biol. Chem. 2005, 280, 22670–22678. [Google Scholar] [CrossRef][Green Version]
- Baba, M.; Nakajo, S.; Tu, P.H.; Tomita, T.; Nakaya, K.; Lee, V.M.; Trojanowski, J.Q.; Iwatsubo, T. Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 1998, 152, 879–884. [Google Scholar]
- Crocker, S.J.; Smith, P.D.; Jackson-Lewis, V.; Lamba, W.R.; Hayley, S.P.; Grimm, E.; Callaghan, S.M.; Slack, R.S.; Melloni, E.; Przedborski, S.; et al. Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J. Neurosci. 2003, 23, 4081–4091. [Google Scholar] [CrossRef] [PubMed]
- Dufty, B.M.; Warner, L.R.; Hou, S.T.; Jiang, S.X.; Gomez-Isla, T.; Leenhouts, K.M.; Oxford, J.T.; Feany, M.B.; Masliah, E.; Rohn, T.T. Calpain-cleavage of α-synuclein: Connecting proteolytic processing to disease-linked aggregation. Am. J. Pathol. 2007, 170, 1725–1738. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Diepenbroek, M.; Casadei, N.; Esmer, H.; Saido, T.C.; Takano, J.; Kahle, P.J.; Nixon, R.A.; Rao, M.V.; Melki, R.; Pieri, L.; et al. Overexpression of the calpain-specific inhibitor calpastatin reduces human α-Synuclein processing, aggregation and synaptic impairment in [A30P] α-Syn transgenic mice. Hum. Mol. Genet. 2014, 23, 3975–3989. [Google Scholar] [CrossRef] [PubMed]
- Mishizen-Eberz, A.J.; Guttmann, R.P.; Giasson, B.I.; Day, G.A., 3rd; Hodara, R.; Ischiropoulos, H.; Lee, V.M.; Trojanowski, J.Q.; Lynch, D.R. Distinct cleavage patterns of normal and pathologic forms of α-synuclein by calpain I in vitro. J. Neurochem. 2003, 86, 836–847. [Google Scholar] [CrossRef] [PubMed]
- Mishizen-Eberz, A.J.; Norris, E.H.; Giasson, B.I.; Hodara, R.; Ischiropoulos, H.; Lee, V.M.; Trojanowski, J.Q.; Lynch, D.R. Cleavage of α-synuclein by calpain: Potential role in degradation of fibrillized and nitrated species of α-synuclein. Biochemistry 2005, 44, 7818–7829. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Wang, B.; Hoop, C.L.; Williams, J.K.; Baum, J. Probing acetylated-α-synuclein monomer–aggregate complexes by NMR elucidates mechanism of fibril seeding. bioRxiv 2020. [Google Scholar] [CrossRef]
- Brahmachari, S.; Ge, P.; Lee, S.H.; Kim, D.; Karuppagounder, S.S.; Kumar, M.; Mao, X.; Shin, J.H.; Lee, Y.; Pletnikova, O.; et al. Activation of tyrosine kinase c-Abl contributes to α-Synuclein-induced neurodegeneration. J. Clin. Investig. 2016, 126, 2970–2988. [Google Scholar] [CrossRef][Green Version]
- Hantschel, O.; Superti-Furga, G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat. Rev. Mol. Cell Biol. 2004, 5, 33–44. [Google Scholar] [CrossRef]
- Brahmachari, S.; Karuppagounder, S.S.; Ge, P.; Lee, S.; Dawson, V.L.; Dawson, T.M.; Ko, H.S. c-Abl and Parkinson’s Disease: Mechanisms and Therapeutic Potential. J. Parkinson’s Dis. 2017, 7, 589–601. [Google Scholar] [CrossRef][Green Version]
- Hannestad, J.K.; Rocha, S.; Agnarsson, B.; Zhdanov, V.P.; Wittung-Stafshede, P.; Höök, F. Single-vesicle imaging reveals lipid-selective and stepwise membrane disruption by monomeric α-synuclein. Proc. Natl. Acad. Sci. USA 2020, 117, 14178–14186. [Google Scholar] [CrossRef]
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Aspholm, E.E.; Matečko-Burmann, I.; Burmann, B.M. Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States? Life 2020, 10, 289. https://doi.org/10.3390/life10110289
Aspholm EE, Matečko-Burmann I, Burmann BM. Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States? Life. 2020; 10(11):289. https://doi.org/10.3390/life10110289
Chicago/Turabian StyleAspholm, Emelie E., Irena Matečko-Burmann, and Björn M. Burmann. 2020. "Keeping α-Synuclein at Bay: A More Active Role of Molecular Chaperones in Preventing Mitochondrial Interactions and Transition to Pathological States?" Life 10, no. 11: 289. https://doi.org/10.3390/life10110289