Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy
Abstract
:1. Introduction
2. Material and Methods
2.1. Source of Brain Tissue
2.2. Immunohistochemistry
2.3. Immunohistochemistry Analysis and Pathology Grading in PD and MSA
2.4. Statistical Analysis Methods and Representation of Data
3. Results
3.1. α-Synuclein Pathology in PD
3.2. Unmodified α-Synuclein (UN)
3.3. pS87 α-Synuclein
3.4. pS129 α-Synuclein
3.5. nY39 α-Synuclein
3.6. Differential Co-Occurrence of the α-Synuclein PTMs in Lewy Pathologies
3.6.1. LBs
3.6.2. LNs
3.7. α-Synuclein Pathology in MSA
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Reeve, A.; Simcox, E.; Turnbull, D. Ageing and Parkinson’s disease: Why is advancing age the biggest risk factor? Ageing Res. Rev. 2014, 14, 19–30. [Google Scholar] [CrossRef] [PubMed]
- Gibb, W.R.; Scott, T.; Lees, A.J. Neuronal inclusions of Parkinson’s disease. Mov. Disord. 1991, 6, 2–11. [Google Scholar] [CrossRef] [PubMed]
- Schapira, A.H.V.; Chaudhuri, K.R.; Jenner, P. Erratum: Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 2017, 18, 509. [Google Scholar] [CrossRef] [PubMed]
- Hernandez, D.G.; Reed, X.; Singleton, A.B. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 2016, 139, 59–74. [Google Scholar] [CrossRef] [PubMed]
- Grenn, F.P.; Kim, J.J.; Makarious, M.B.; Iwaki, H.; Illarionova, A.; Brolin, K.; Kluss, J.H.; Schumacher-Schuh, A.F.; Leonard, H.; Faghri, F.; et al. The Parkinson’s Disease Genome-Wide Association Study Locus Browser. Mov. Disord. 2020, 35, 2056–2067. [Google Scholar] [CrossRef]
- Nalls, M.A.; Blaunwendraat, C.; Vallerga, C.L.; Heilbron, K.; Bandres-Ciga, S.; Chang, D.; Tan, M.; Kia, D.A.; Noyce, A.J.; Xue, A.; et al. Identification of novel risk-loci, causal insights, and heritable risk for Parkinson’s disease: A meta analysis of genome-wide association studies. Lancet Neurol. 2019, 139, 59–74. [Google Scholar] [CrossRef]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 1998, 95, 6469–6473. [Google Scholar] [CrossRef] [Green Version]
- Braak, H.; Del Tredici, K.; Rüb, U.; de Vos, R.A.; Steur, E.N.J.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 2003, 24, 197–211. [Google Scholar] [CrossRef]
- Ma, J.; Gao, J.; Wang, J.; Xie, A. Prion-Like Mechanisms in Parkinson’s Disease. Front. Neurosci. 2019, 13, 552. [Google Scholar] [CrossRef]
- Jellinger, K.A. Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy. J. Alzheimer’s Dis. 2018, 62, 1141–1179. [Google Scholar] [CrossRef] [Green Version]
- Ahmed, Z.; Asi, Y.T.; Sailer, A.; Lees, A.J.; Houlden, H.; Revesz, T.; Holton, J.L. The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol. Appl. Neurobiol. 2012, 38, 4–24. [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. 2012, 14, 38–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, W.S.; Kågedal, K.; Halliday, G.M. Alpha-synuclein biology in Lewy body diseases. Alzheimer’s Res. Ther. 2014, 6, 73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beyer, K.; Ariza, A. Alpha-Synuclein Posttranslational Modification and Alternative Splicing as a Trigger for Neurodegeneration. Mol. Neurobiol. 2013, 47, 509–524. [Google Scholar] [CrossRef]
- Barrett, P.J.; Greenamyre, J.T. Post-translational modification of α-synuclein in Parkinson’s disease. Brain Res. 2015, 1628 Pt B, 247–253. [Google Scholar] [CrossRef]
- Okochi, M.; Walter, J.; Koyama, A.; Nakajo, S.; Baba, M.; Iwatsubo, T.; Meijer, L.; Kahle, P.J.; Haass, C. Constitutive Phosphorylation of the Parkinson’s Disease Associated α-Synuclein. J. Biol. Chem. 2000, 275, 390–397. [Google Scholar] [CrossRef] [Green Version]
- Anderson, J.P.; Walker, D.E.; Goldstein, J.M.; de Laat, R.; Banducci, K.; Caccavello, R.J.; Barbour, R.; Huang, J.; Kling, K.; Lee, M.; et al. Phosphorylation of Ser-129 Is the Dominant Pathological Modification of α-Synuclein in Familial and Sporadic Lewy Body Disease. J. Biol. Chem. 2006, 281, 29739–29752. [Google Scholar] [CrossRef] [Green Version]
- Nishie, M.; Mori, F.; Yoshimoto, M.; Takahashi, H.; Wakabayashi, K. A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol. Appl. Neurobiol. 2004, 30, 546–554. [Google Scholar] [CrossRef]
- Waxman, E.; Mazzulli, J.R.; Giasson, B.I. Characterization of Hydrophobic Residue Requirements for α-Synuclein Fibrillization. Biochem. 2009, 48, 9427–9436. [Google Scholar] [CrossRef] [Green Version]
- Paleologou, K.E.; Oueslati, A.; Shakked, G.; Rospigliosi, C.C.; Kim, H.-Y.; Lamberto, G.R.; Fernandez, C.O.; Schmid, A.; Chegini, F.; Gai, W.P.; et al. Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits -Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions. J. Neurosci. 2010, 30, 3184–3198. [Google Scholar] [CrossRef]
- Oueslati, A.; Paleologou, K.E.; Schneider, B.; Aebischer, P.; Lashuel, H.A. Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human-Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson’s Disease. J. Neurosci. 2012, 32, 1536–1544. [Google Scholar] [CrossRef] [Green Version]
- Dias, V.; Junn, E.; Mouradian, M.M. The Role of Oxidative Stress in Parkinson’s Disease. J. Park. Dis. 2013, 3, 461–491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Horowitz, M.P.; Milanese, C.; Di Maio, R.; Hu, X.; Montero, L.M.; Sanders, L.H.; Tapias, V.; Sepe, S.; Van Cappellen, W.A.; Burton, E.; et al. Single-Cell Redox Imaging Demonstrates a Distinctive Response of Dopaminergic Neurons to Oxidative Insults. Antioxid. Redox Signal. 2011, 15, 855–871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Duda, J.E.; Giasson, B.; Chen, Q.; Gur, T.L.; Hurtig, H.I.; Stern, M.B.; Gollomp, S.M.; Ischiropoulos, H.; Lee, V.M.-Y.; Trojanowski, J.Q. Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am. J. Pathol. 2000, 157, 1439–1945. [Google Scholar] [CrossRef] [Green Version]
- Burai, R.; Ait-Bouziad, N.; Chiki, A.; Lashuel, H.A. Elucidating the Role of Site-Specific Nitration of α-Synuclein in the Pathogenesis of Parkinson’s Disease via Protein Semisynthesis and Mutagenesis. J. Am. Chem. Soc. 2015, 137, 5041–5052. [Google Scholar] [CrossRef]
- Burre, J. The Synaptic Function of α-Synuclein. J. Park. Dis. 2015, 5, 699–713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sevcsik, E.; Trexler, A.J.; Dunn, J.M.; Rhoades, E. Allostery in a Disordered Protein: Oxidative Modifications to α-Synuclein Act Distally To Regulate Membrane Binding. J. Am. Chem. Soc. 2011, 133, 7152–7158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McKeith, I.G.; Dickson, D.W.; Lowe, J.; Emre, M.; O’Brien, J.T.; Feldman, H.; Cummings, J.; Duda, J.E.; Lippa, C.; Perry, E.K.; et al. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium. Neurology 2005, 65, 1863–1872. [Google Scholar] [CrossRef] [Green Version]
- Manzanza, N.D.O.; Sedlackova, L.; Kalaria, R.N. Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders. Front. Aging Neurosci. 2021, 13, 690293. [Google Scholar] [CrossRef]
- Volpicelli-Daley, L.A.; Gamble, K.; Schultheiss, C.E.; Riddle, D.M.; West, A.; Lee, V.M.-Y. Formation of alpha-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 2014, 25, 4010–4023. [Google Scholar] [CrossRef]
- Perlson, E.; Maday, S.; Fu, M.-M.; Moughamian, A.J.; Holzbaur, E.L. Retrograde axonal transport: Pathways to cell death? Trends Neurosci. 2010, 33, 335–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fujiwara, H.; Hasegawa, M.; Dohmae, N.; Kawashima, A.; Masliah, E.; Goldberg, M.S.; Shen, J.; Takio, K.; Iwatsubo, T. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 2002, 4, 160–164. [Google Scholar] [CrossRef] [PubMed]
- Shahmoradian, S.H.; Lewis, A.J.; Genoud, C.; Hench, J.; Moors, T.E.; Navarro, P.P.; Castano-Diez, 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] [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]
- Giasson, B.I.; Duda, J.E.; Murray, I.V.J.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M.-Y. Oxidative Damage Linked to Neurodegeneration by Selective α-Synuclein Nitration in Synucleinopathy Lesions. Science 2000, 290, 985–989. [Google Scholar] [CrossRef]
- Paxinou, E.; Chen, Q.; Weisse, M.; Giasson, B.I.; Norris, E.H.; Rueter, S.M.; Trojanowski, J.Q.; Lee, V.M.-Y.; Ischiropoulos, H. Induction of α-Synuclein Aggregation by Intracellular Nitrative Insult. J. Neurosci. 2001, 21, 8053–8061. [Google Scholar] [CrossRef]
- Hodara, R.; Norris, E.; Giasson, B.I.; Mishizen-Eberz, A.J.; Lynch, D.R.; Lee, V.M.-Y.; Ischiropoulos, H. Functional Consequences of α-Synuclein Tyrosine Nitration. J. Biol. Chem. 2004, 279, 47746–47753. [Google Scholar] [CrossRef] [Green Version]
- Compagnoni, G.M.; Di Fonzo, A. Understanding the pathogenesis of multiple system atrophy: State of the art and future perspectives. Acta Neuropathol. Commun. 2019, 7, 113. [Google Scholar] [CrossRef] [Green Version]
- Stefanis, L. Alpha-Synuclein in Parkinson’s Disease. Cold Spring Harb. Perspect. Med. 2011, 2, a009399. [Google Scholar] [CrossRef] [Green Version]
- Hass, E.W.; Sorrentino, Z.A.; Xia, Y.; Lloyd, G.M.; Trojanowski, J.Q.; Prokop, S.; Giasson, B.I. Disease-, region- and cell type specific diversity of α-synuclein carboxy terminal truncations in synucleinopathies. Acta Neuropathol. Commun. 2021, 9, 146. [Google Scholar] [CrossRef]
Case Patient (P)/Control (C) | Gender (M/F) | Age at Death (Years) | Postmortem Delay (h:min) | Diagnosis |
---|---|---|---|---|
P | F | 83 | 19:00 | IPD BStem |
P | M | 81 | 51:00 | IPD BStem |
P | F | 83 | 99:00 | IPD BStem |
P | M | 74 | 19.05 | IPD BStem |
P | M | 75 | 29:31 | IPD BStem |
P | M | 84 | 75:05 | IPD Limbic |
P | F | 80 | 39:10 | IPD Limbic |
P | M | 78 | 54:55 | IPD Limbic |
P | M | 93 | 82:20 | IPD Limbic |
P | F | 72 | 79:40 | IPD Limbic |
P | M | 72 | 100:20 | IPD Neocortical |
P | M | 81 | 33:25 | IPD Neocortical |
P | M | 81 | 73:15 | IPD Neocortical |
P | F | 76 | 87:05 | IPD Neocortical |
P | F | 76 | 76:15 | IPD Neocortical |
P | F | 80 | 23:20 | MSA |
P | M | 50 | 6:15 | MSA |
P | F | 65 | 10.25 | MSA |
P | F | 60 | 9:30 | MSA |
P | M | 69 | 43:15 | MSA |
C | M | 76 | 76:00 | Control |
C | F | 84 | 84:00 | Control |
C | M | 80 | 80:00 | Control |
C | M | 83 | 83:15 | Control |
C | F | 91 | 91:00 | Control |
C | M | 76 | 76:00 | Control |
Antibodies | Source/Cat No. or Clone | Host and Clonality | Antibody Dilution Used | Incubation Time |
---|---|---|---|---|
anti-alpha-synuclein (epitope: aa100 to C-terminal) | Abcam/ab15530 | Rabbit polyclonal | 1 in 500 | o/n at 4 °C |
anti-alpha-synuclein (phosphorylated S87) | Hilal Lashuel/Lash-pS87 | Rabbit polyclonal | 1 in 500 | 1 h at RT |
anti-alpha-synuclein (phosphorylated S129) | Biolegend/P-syn-81A | Mouse monoclonal | 1 in 500 | 1 h at RT |
anti-alpha-synuclein (nitrated Y39) | Hilal Lashuel/Lash-EGT-nY39 | Rabbit polyclonal | 1 in 500 | o/n at 4 °C |
(A) | |
Number of LBs in 20× Field | Corresponding Grade of Pathology |
0 | None |
1 | Grade 1 (mild) |
2–5 | Grade 2 (moderate) |
6–9 | Grade 3 (severe) |
>10 | Grade 4 (very severe) |
(B) | |
Number of LNs in 20× Field | Corresponding Grade of Pathology |
0 | 0 (−) |
1–4 | 1 (+) |
5–9 | Grade 2 (++) |
>10 | Grade 3 (+++) |
Synucleinopathy | Type of Inclusion | |||
---|---|---|---|---|
α-Synuclein (UN) | pS87 α-Synuclein | pS129 α-Synuclein | nY39 α-Synuclein | |
IPD | LBs, FLNs, TLNs, dot-like structures | Some LBs and LNs | LBs, FLNs, TLNs, dot-like structures | Some LBs, FLNs, TLNs, dot-like structures |
MSA | GCIs, NCIs, NNIs, threads | Mainly GCIs and some threads | GCIs, NCIs, NNIs, threads, dot-like structures | GCIs, NCIs, NNIs, threads, dot-like structures |
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Sonustun, B.; Altay, M.F.; Strand, C.; Ebanks, K.; Hondhamuni, G.; Warner, T.T.; Lashuel, H.A.; Bandopadhyay, R. Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy. Cells 2022, 11, 906. https://doi.org/10.3390/cells11050906
Sonustun B, Altay MF, Strand C, Ebanks K, Hondhamuni G, Warner TT, Lashuel HA, Bandopadhyay R. Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy. Cells. 2022; 11(5):906. https://doi.org/10.3390/cells11050906
Chicago/Turabian StyleSonustun, Berkiye, Melek Firat Altay, Catherine Strand, Kirsten Ebanks, Geshanthi Hondhamuni, Thomas T. Warner, Hilal A. Lashuel, and Rina Bandopadhyay. 2022. "Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy" Cells 11, no. 5: 906. https://doi.org/10.3390/cells11050906
APA StyleSonustun, B., Altay, M. F., Strand, C., Ebanks, K., Hondhamuni, G., Warner, T. T., Lashuel, H. A., & Bandopadhyay, R. (2022). Pathological Relevance of Post-Translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy. Cells, 11(5), 906. https://doi.org/10.3390/cells11050906