α-Synuclein Modulates Tau Spreading in Mouse Brains

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2020 Oct 22

PMID 33091110

Citations 37

Authors

Fares Bassil

Emily S Meymand

Hannah J Brown

Hong Xu

Timothy O Cox

Shankar Pattabhiraman

Chantal M Maghames

Qihui Wu

Bin Zhang

John Q Trojanowski

Virginia M-Y Lee

Affiliations

Soon will be listed here.

Abstract

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.

Citing Articles

Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health.

Uytterhoeven V, Verstreken P, Nachman E J Cell Biol. 2024; 224(2).

PMID: 39718548 PMC: 11668179. DOI: 10.1083/jcb.202409104.

Amygdala-predominant α-synuclein pathology is associated with exacerbated hippocampal neuron loss in Alzheimer's disease.

Gawor K, Tome S, Vandenberghe R, Van Damme P, Vandenbulcke M, Otto M Brain Commun. 2024; 6(6):fcae442.

PMID: 39659977 PMC: 11631359. DOI: 10.1093/braincomms/fcae442.

Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.

Jiang L, Zhang X, Hu H Int J Mol Sci. 2024; 25(22).

PMID: 39596445 PMC: 11594478. DOI: 10.3390/ijms252212380.

Liquid-liquid phase separation and conformational strains of -Synuclein: implications for Parkinson's disease pathogenesis.

Ruiz-Ortega E, Wilkaniec A, Adamczyk A Front Mol Neurosci. 2024; 17:1494218.

PMID: 39507104 PMC: 11537881. DOI: 10.3389/fnmol.2024.1494218.

Multivalency drives interactions of alpha-synuclein fibrils with tau.

Ramirez J, Saleh I, Yanagawa E, Shimogawa M, Brackhahn E, Petersson E PLoS One. 2024; 19(9):e0309416.

PMID: 39255305 PMC: 11386428. DOI: 10.1371/journal.pone.0309416.

References

Bennett R, DeVos S, Dujardin S, Corjuc B, Gor R, Gonzalez J . Enhanced Tau Aggregation in the Presence of Amyloid β. Am J Pathol. 2017; 187(7):1601-1612. PMC: 5500829. DOI: 10.1016/j.ajpath.2017.03.011. View

Bachhuber T, Katzmarski N, McCarter J, Loreth D, Tahirovic S, Kamp F . Inhibition of amyloid-β plaque formation by α-synuclein. Nat Med. 2015; 21(7):802-7. DOI: 10.1038/nm.3885. View

Ono K, Takahashi R, Ikeda T, Yamada M . Cross-seeding effects of amyloid β-protein and α-synuclein. J Neurochem. 2012; 122(5):883-90. DOI: 10.1111/j.1471-4159.2012.07847.x. View

Deleidi M, Maetzler W . Protein clearance mechanisms of alpha-synuclein and amyloid-Beta in lewy body disorders. Int J Alzheimers Dis. 2012; 2012:391438. PMC: 3485523. DOI: 10.1155/2012/391438. View

Marui W, Iseki E, Ueda K, Kosaka K . Occurrence of human alpha-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer's disease. J Neurol Sci. 2000; 174(2):81-4. DOI: 10.1016/s0022-510x(99)00327-5. View

Oh S, Harris J, Ng L, Winslow B, Cain N, Mihalas S . A mesoscale connectome of the mouse brain. Nature. 2014; 508(7495):207-14. PMC: 5102064. DOI: 10.1038/nature13186. View

Sharma A, Bruce K, Chen B, Gyoneva S, Behrens S, Bommarius A . Contributions of the Prion Protein Sequence, Strain, and Environment to the Species Barrier. J Biol Chem. 2015; 291(3):1277-88. PMC: 4714215. DOI: 10.1074/jbc.M115.684100. View

Frasier M, WALZER M, McCarthy L, Magnuson D, Lee J, Haas C . Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol. 2005; 192(2):274-87. DOI: 10.1016/j.expneurol.2004.07.016. View

Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M . beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001; 98(21):12245-50. PMC: 59799. DOI: 10.1073/pnas.211412398. View

10.

Guo J, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B . Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016; 213(12):2635-2654. PMC: 5110027. DOI: 10.1084/jem.20160833. View

11.

Jellinger K, Attems J . Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol. 2008; 115(4):427-36. DOI: 10.1007/s00401-008-0347-5. View

12.

Wersinger C, Sidhu A . Disruption of the interaction of alpha-synuclein with microtubules enhances cell surface recruitment of the dopamine transporter. Biochemistry. 2005; 44(41):13612-24. DOI: 10.1021/bi050402p. View

13.

Rey N, Steiner J, Maroof N, Luk K, Madaj Z, Trojanowski J . Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease. J Exp Med. 2016; 213(9):1759-78. PMC: 4995088. DOI: 10.1084/jem.20160368. View

14.

Kawakami F, Suzuki M, Shimada N, Kagiya G, Ohta E, Tamura K . Stimulatory effect of α-synuclein on the tau-phosphorylation by GSK-3β. FEBS J. 2011; 278(24):4895-904. DOI: 10.1111/j.1742-4658.2011.08389.x. View

15.

Luk K, Kehm V, Carroll J, Zhang B, OBrien P, Trojanowski J . Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012; 338(6109):949-53. PMC: 3552321. DOI: 10.1126/science.1227157. View

16.

Duka T, Duka V, Joyce J, Sidhu A . Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models. FASEB J. 2009; 23(9):2820-30. PMC: 2796901. DOI: 10.1096/fj.08-120410. View

17.

Bassil F, Brown H, Pattabhiraman S, Iwasyk J, Maghames C, Meymand E . Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. Neuron. 2019; 105(2):260-275.e6. PMC: 6981053. DOI: 10.1016/j.neuron.2019.10.010. View

18.

Lashley T, Holton J, Gray E, Kirkham K, OSullivan S, Hilbig A . Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients. Acta Neuropathol. 2008; 115(4):417-25. DOI: 10.1007/s00401-007-0336-0. View

19.

Duka T, Rusnak M, Drolet R, Duka V, Wersinger C, Goudreau J . Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism. FASEB J. 2006; 20(13):2302-12. DOI: 10.1096/fj.06-6092com. View

20.

Guo J, Covell D, Daniels J, Iba M, Stieber A, Zhang B . Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013; 154(1):103-17. PMC: 3820001. DOI: 10.1016/j.cell.2013.05.057. View