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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2024

Open Access 01-12-2024 | Parkinson's Disease | Review

Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration

Authors: Wen Li, Jia-Yi Li

Published in: Translational Neurodegeneration | Issue 1/2024

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Abstract

Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one of the most significant pathological features of neurodegenerative diseases. Tauopathies, represented by Alzheimer’s disease (AD), and synucleinopathies, represented by Parkinson’s disease (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia is also a major sign of advanced PD. We and other researchers have sequentially shown the cross-seeding phenomenon of α-synuclein (α-syn) and tau, reinforcing pathologies between synucleinopathies and tauopathies. The highly overlapping clinical and pathological features imply shared pathogenic mechanisms between the two groups of disease. The diagnostic and therapeutic strategies seemingly appropriate for one distinct neurodegenerative disease may also apply to a broader spectrum. Therefore, a clear understanding of the overlaps and divergences between tauopathy and synucleinopathy is critical for unraveling the nature of the complicated associations among neurodegenerative diseases. In this review, we discuss the shared and diverse characteristics of tauopathies and synucleinopathies from aspects of genetic causes, clinical manifestations, pathological progression and potential common therapeutic approaches targeting the pathology, in the aim to provide a timely update for setting the scheme of disease classification and provide novel insights into the therapeutic development for neurodegenerative diseases.
Literature
1.
Gotz J, Halliday G, Nisbet RM. Molecular pathogenesis of the tauopathies. Annu Rev Pathol. 2019;14:239–61.PubMedCrossRef
2.
3.
Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A. 1997;94(8):4113–8.PubMedPubMedCentralCrossRef
4.
5.
6.
7.
Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener. 2019;14(1):5.PubMedPubMedCentralCrossRef
8.
9.
Goedert M, Spillantini MG. Lewy body diseases and multiple system atrophy as alpha-synucleinopathies. Mol Psychiatry. 1998;3(6):462–5.PubMedCrossRef
10.
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601.PubMedCrossRef
11.
Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41(12):1308–12.PubMedPubMedCentralCrossRef
12.
Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41(12):1303–7.PubMedCrossRef
13.
de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, et al. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nat Commun. 2021;12(1):3417.PubMedPubMedCentralCrossRef
14.
Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, et al. A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. 2016;21(1):108–17.PubMedCrossRef
15.
Chen J, Yu JT, Wojta K, Wang HF, Zetterberg H, Blennow K, et al. Genome-wide association study identifies MAPT locus influencing human plasma tau levels. Neurology. 2017;88(7):669–76.PubMedPubMedCentralCrossRef
16.
Wang Q, Tian Q, Song X, Liu Y, Li W. SNCA gene polymorphism may contribute to an increased risk of Alzheimer’s disease. J Clin Lab Anal. 2016;30(6):1092–9.PubMedPubMedCentralCrossRef
17.
Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17(1):64–74.PubMedCrossRef
18.
Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53(3):294–303.PubMedPubMedCentralCrossRef
19.
Li YJ, Hauser MA, Scott WK, Martin ER, Booze MW, Qin XJ, et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology. 2004;62(11):2005–9.PubMedCrossRef
20.
Real R, Martinez-Carrasco A, Reynolds RH, Lawton MA, Tan MMX, Shoai M, et al. Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia. Brain. 2023;146(5):1873–87.PubMedCrossRef
21.
Szeto JYY, Walton CC, Rizos A, Martinez-Martin P, Halliday GM, Naismith SL, et al. Dementia in long-term Parkinson’s disease patients: a multicentre retrospective study. NPJ Parkinsons Dis. 2020;6:2.PubMedPubMedCentralCrossRef
22.
23.
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95(13):7737–41.PubMedPubMedCentralCrossRef
24.
Pan L, Li C, Meng L, Tian Y, He M, Yuan X, et al. Tau accelerates alpha-synuclein aggregation and spreading in Parkinson’s disease. Brain. 2022;145(10):3454–71.PubMedCrossRef
25.
Abeliovich A, Gitler AD. Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature. 2016;539(7628):207–16.PubMedCrossRef
26.
Kon T, Tomiyama M, Wakabayashi K. Neuropathology of Lewy body disease: Clinicopathological crosstalk between typical and atypical cases. Neuropathology. 2020;40(1):30–9.PubMedCrossRef
27.
Hishikawa N, Hashizume Y, Yoshida M, Sobue G. Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol. 2003;105(4):341–50.PubMedCrossRef
28.
Monzio Compagnoni G, Di Fonzo A. Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives. Acta Neuropathol Commun. 2019;7(1):113.PubMedPubMedCentralCrossRef
29.
Jellinger KA. Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord. 2014;29(14):1720–41.PubMedCrossRef
30.
Wang XJ, Ma MM, Zhou LB, Jiang XY, Hao MM, Teng RKF, et al. Autonomic ganglionic injection of alpha-synuclein fibrils as a model of pure autonomic failure alpha-synucleinopathy. Nat Commun. 2020;11(1):934.PubMedPubMedCentralCrossRef
31.
Valentino RR, Koga S, Walton RL, Soto-Beasley AI, Kouri N, DeTure MA, et al. MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features. Acta Neuropathol Commun. 2020;8(1):218.PubMedPubMedCentralCrossRef
32.
Tamvaka N, Manne S, Kondru N, Ross OA. Pick’s disease, seeding an answer to the clinical diagnosis conundrum. Biomedicines. 2023;11(6):16464.CrossRef
33.
Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: The Movement Disorder Society Criteria. Mov Disord. 2017;32(6):853–64.PubMedPubMedCentralCrossRef
34.
Bieniek KF, Ross OA, Cormier KA, Walton RL, Soto-Ortolaza A, Johnston AE, et al. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol. 2015;130(6):877–89.PubMedPubMedCentralCrossRef
35.
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013;136(Pt 1):43–64.PubMedCrossRef
36.
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014;128(6):755–66.PubMedPubMedCentralCrossRef
37.
38.
Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet. 2008;40(9):1076–83.PubMedPubMedCentralCrossRef
39.
Pittman AM, Myers AJ, Abou-Sleiman P, Fung HC, Kaleem M, Marlowe L, et al. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet. 2005;42(11):837–46.PubMedPubMedCentralCrossRef
40.
41.
Zhang CC, Xing A, Tan MS, Tan L, Yu JT. The role of MAPT in neurodegenerative diseases: genetics, mechanisms and therapy. Mol Neurobiol. 2016;53(7):4893–904.PubMedCrossRef
42.
43.
44.
Llado A, Ezquerra M, Sanchez-Valle R, Rami L, Tolosa E, Molinuevo JL. A novel MAPT mutation (P301T) associated with familial frontotemporal dementia. Eur J Neurol. 2007;14(8):e9-10.PubMedCrossRef
45.
Erro ME, Zelaya MV, Mendioroz M, Larumbe R, Ortega-Cubero S, Lanciego JL, et al. Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings. J Neurol. 2019;266(10):2396–405.PubMedCrossRef
46.
Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, et al. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain. 1999;122(Pt 4):741–56.PubMedCrossRef
47.
Ogaki K, Li Y, Takanashi M, Ishikawa K, Kobayashi T, Nonaka T, et al. Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism Relat Disord. 2013;19(1):15–20.PubMedCrossRef
48.
Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, et al. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol. 2002;52(4):511–6.PubMedCrossRef
49.
Arienti F, Lazzeri G, Vizziello M, Monfrini E, Bresolin N, Saetti MC, et al. Unravelling genetic factors underlying corticobasal syndrome: a systematic review. Cells. 2021;10(1):171.PubMedPubMedCentralCrossRef
50.
Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019;294(48):18488–503.PubMedPubMedCentralCrossRef
51.
Pihlstrom L, Toft M. Genetic variability in SNCA and Parkinson’s disease. Neurogenetics. 2011;12(4):283–93.PubMedCrossRef
52.
53.
Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol. 1990;27(3):276–82.PubMedCrossRef
54.
Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem. 2005;280(9):7800–7.PubMedCrossRef
55.
Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul-Mellier AL, Ruggeri FS, et al. The H50Q mutation enhances alpha-synuclein aggregation, secretion, and toxicity. J Biol Chem. 2014;289(32):21856–76.PubMedPubMedCentralCrossRef
56.
Rutherford NJ, Moore BD, Golde TE, Giasson BI. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of alpha-synuclein. J Neurochem. 2014;131(6):859–67.PubMedCrossRef
57.
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;18(2):106–8.PubMedCrossRef
58.
Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet. 2004;364(9440):1167–9.PubMedCrossRef
59.
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science (New York, NY). 2003;302(5646):841.CrossRef
60.
Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, 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;18(12):1091–102.PubMedPubMedCentralCrossRef
61.
Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, et al. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson’s and Alzheimer’s diseases. Neurobiol Aging. 2016;38(214):e7–10.
62.
van Rheenen W, van der Spek RAA, Bakker MK, van Vugt J, Hop PJ, Zwamborn RAJ, et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636–48.PubMedPubMedCentralCrossRef
63.
Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, et al. Tau and alpha-synuclein in susceptibility to, and dementia in Parkinson’s disease. Ann Neurol. 2007;62(2):145–53.PubMedCrossRef
64.
Henderson MX, Sengupta M, Trojanowski JQ, Lee VMY. Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease. Acta Neuropathol Commun. 2019;7(1):183.PubMedPubMedCentralCrossRef
65.
Lee VM, Giasson BI, Trojanowski JQ. More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci. 2004;27(3):129–34.PubMedCrossRef
66.
Jellinger KA. Absence of alpha-synuclein pathology in postencephalitic parkinsonism. Acta Neuropathol. 2009;118(3):371–9.PubMedCrossRef
67.
Moussaud S, Jones DR, Moussaud-Lamodiere EL, Delenclos M, Ross OA, McLean PJ. Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegener. 2014;9:43.PubMedPubMedCentralCrossRef
68.
Cartelli D, Cappelletti G. Microtubule destabilization paves the way to Parkinson’s disease. Mol Neurobiol. 2017;54(9):6762–74.PubMedCrossRef
69.
Stolp Andersen M, Tan M, Holtman IR, Hardy J, International Parkinson’s Disease Genomics C, Pihlstrom L. Dissecting the limited genetic overlap of Parkinson’s and Alzheimer’s disease. Ann Clin Transl Neurol. 2022;9(8):1289–95.CrossRef
70.
Arneson D, Zhang Y, Yang X, Narayanan M. Shared mechanisms among neurodegenerative diseases: from genetic factors to gene networks. J Genet. 2018;97(3):795–806.PubMedPubMedCentralCrossRef
71.
Korn L, Speicher AM, Schroeter CB, Gola L, Kaehne T, Engler A, et al. MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD. Redox Biol. 2023;59: 102597.PubMedCrossRef
72.
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3(4):519–26.PubMedCrossRef
73.
Brunello CA, Merezhko M, Uronen RL, Huttunen HJ. Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci. 2020;77(9):1721–44.PubMedCrossRef
74.
Chhatwal JP, Schultz AP, Dang Y, Ostaszewski B, Liu L, Yang HS, et al. Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals. Nat Commun. 2020;11(1):6024.PubMedPubMedCentralCrossRef
75.
Zhang X, Vigers M, McCarty J, Rauch JN, Fredrickson GH, Wilson MZ, et al. The proline-rich domain promotes Tau liquid-liquid phase separation in cells. J Cell Biol. 2020;219(11):e202006054.PubMedPubMedCentralCrossRef
76.
77.
Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. 2018;7:e36584.PubMedPubMedCentralCrossRef
78.
79.
Tracy TE, Madero-Perez J, Swaney DL, Chang TS, Moritz M, Konrad C, et al. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022;185(4):712-28 e14.PubMedPubMedCentralCrossRef
80.
Kellogg EH, Hejab NMA, Poepsel S, Downing KH, DiMaio F, Nogales E. Near-atomic model of microtubule-tau interactions. Science (New York, NY). 2018;360(6394):1242–6.CrossRef
81.
Goedert M, Spillantini MG. Propagation of Tau aggregates. Mol. Brain. 2017;10(1):18.
82.
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature. 2017;547(7662):185–90.PubMedPubMedCentralCrossRef
83.
Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702–5.PubMedCrossRef
84.
Despres C, Byrne C, Qi H, Cantrelle FX, Huvent I, Chambraud B, et al. Identification of the Tau phosphorylation pattern that drives its aggregation. Proc Natl Acad Sci U S A. 2017;114(34):9080–5.PubMedPubMedCentralCrossRef
85.
Xia Y, Prokop S, Gorion KM, Kim JD, Sorrentino ZA, Bell BM, et al. Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer’s disease and other tauopathies. Acta Neuropathol Commun. 2020;8(1):88.PubMedPubMedCentralCrossRef
86.
Lu J, Zhang S, Ma X, Jia C, Liu Z, Huang C, et al. Structural basis of the interplay between alpha-synuclein and Tau in regulating pathological amyloid aggregation. J Biol Chem. 2020;295(21):7470–80.PubMedPubMedCentralCrossRef
87.
88.
Li Y, Zhao C, Luo F, Liu Z, Gui X, Luo Z, et al. Amyloid fibril structure of alpha-synuclein determined by cryo-electron microscopy. Cell Res. 2018;28(9):897–903.PubMedPubMedCentralCrossRef
89.
90.
Cremades N, Dobson CM. The contribution of biophysical and structural studies of protein self-assembly to the design of therapeutic strategies for amyloid diseases. Neurobiol Dis. 2018;109(Pt B):178–90.PubMedCrossRef
91.
Hijaz BA, Volpicelli-Daley LA. Initiation and propagation of alpha-synuclein aggregation in the nervous system. Mol Neurodegener. 2020;15(1):19.PubMedCrossRef
92.
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4.PubMedCrossRef
93.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40.PubMedCrossRef
94.
Li W, Englund E, Widner H, Mattsson B, van Westen D, Latt J, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016;113(23):6544–9.PubMedPubMedCentralCrossRef
95.
Li J-Y, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. J Park Dis. 2008;14(5):501–3.
96.
97.
Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121(2):171–81.PubMedCrossRef
98.
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112(4):389–404.PubMedPubMedCentralCrossRef
99.
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211.PubMedCrossRef
100.
Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396(1):67–72.PubMedCrossRef
101.
Chen QQ, Haikal C, Li W, Li MT, Wang ZY, Li JY. Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson’s disease. Transl Neurodegener. 2018;7:13.PubMedPubMedCentralCrossRef
102.
Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and alpha-synuclein in neurodegeneration. Brain. 2017;140(2):266–78.PubMedCrossRef
103.
Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121(2):715–25.PubMedPubMedCentralCrossRef
104.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–13.PubMedPubMedCentralCrossRef
105.
Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57–71.PubMedPubMedCentralCrossRef
106.
Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR, et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106(47):20051–6.PubMedPubMedCentralCrossRef
107.
108.
Tardivel M, Begard S, Bousset L, Dujardin S, Coens A, Melki R, et al. Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies. Acta Neuropathol Commun. 2016;4(1):117.PubMedPubMedCentralCrossRef
109.
Chakraborty R, Nonaka T, Hasegawa M, Zurzolo C. Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of alpha-Synuclein and mitochondria. Cell Death Dis. 2023;14(5):329.PubMedPubMedCentralCrossRef
110.
Chen K, Martens YA, Meneses A, Ryu DH, Lu W, Raulin AC, et al. LRP1 is a neuronal receptor for alpha-synuclein uptake and spread. Mol Neurodegener. 2022;17(1):57.PubMedPubMedCentralCrossRef
111.
Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020;580(7803):381–5.PubMedPubMedCentralCrossRef
112.
Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science (New York, NY). 2016;353(6307):aah3374.PubMedCentralCrossRef
113.
114.
Patani R, Hardingham GE, Liddelow SA. Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat Rev Neurol. 2023;19(7):395–409.PubMedCrossRef
115.
Liu YJ, Ding Y, Yin YQ, Xiao H, Hu G, Zhou JW. Cspg4(high) microglia contribute to microgliosis during neurodegeneration. Proc Natl Acad Sci U S A. 2023;120(8): e2210643120.PubMedPubMedCentralCrossRef
116.
Dutta D, Jana M, Paidi RK, Majumder M, Raha S, Dasarathy S, et al. Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease-related mouse models. J Clin Invest. 2023;133(18):e161987.PubMedPubMedCentralCrossRef
117.
Sun Y, Guo Y, Feng X, Jia M, Ai N, Dong Y, et al. The behavioural and neuropathologic sexual dimorphism and absence of MIP-3alpha in tau P301S mouse model of Alzheimer’s disease. J Neuroinflammation. 2020;17(1):72.PubMedPubMedCentralCrossRef
118.
Garcia P, Jurgens-Wemheuer W, Uriarte Huarte O, Michelucci A, Masuch A, Brioschi S, et al. Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease. Glia. 2022;70(5):935–60.PubMedPubMedCentralCrossRef
119.
120.
Risiglione P, Zinghirino F, Di Rosa MC, Magri A, Messina A. Alpha-synuclein and mitochondrial dysfunction in Parkinson’s disease: the emerging role of VDAC. Biomolecules. 2021;11(5):718.PubMedPubMedCentralCrossRef
121.
Roy B, Jackson GR. Interactions between Tau and alpha-synuclein augment neurotoxicity in a Drosophila model of Parkinson’s disease. Hum Mol Genet. 2014;23(11):3008–23.PubMedPubMedCentralCrossRef
122.
Hamano T, Enomoto S, Shirafuji N, Ikawa M, Yamamura O, Yen SH, et al. Autophagy and tau protein. Int J Mol Sci. 2021;22(14).
123.
Tang Q, Gao P, Arzberger T, Hollerhage M, Herms J, Hoglinger G, et al. Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion. Cell Death Dis. 2021;12(10):854.PubMedPubMedCentralCrossRef
124.
125.
126.
Hamilton RL. Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol. 2000;10(3):378–84.PubMedCrossRef
127.
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(23):11282–6.PubMedPubMedCentralCrossRef
128.
Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, et al. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998;153(5):1365–70.PubMedPubMedCentralCrossRef
129.
Uchikado H, Lin WL, DeLucia MW, Dickson DW. Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol. 2006;65(7):685–97.PubMedCrossRef
130.
Toledo JB, Gopal P, Raible K, Irwin DJ, Brettschneider J, Sedor S, et al. Pathological alpha-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathol. 2016;131(3):393–409.PubMedCrossRef
131.
Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, et al. Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Exp Neurol. 2004;187(2):279–88.PubMedCrossRef
132.
Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol. 2003;62(4):389–97.PubMedCrossRef
133.
Arima K, Mizutani T, Alim MA, Tonozuka-Uehara H, Izumiyama Y, Hirai S, et al. NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies. Acta Neuropathol. 2000;100(2):115–21.PubMedCrossRef
134.
Bassil F, Meymand ES, Brown HJ, Xu H, Cox TO, Pattabhiraman S, et al. Alpha-synuclein modulates tau spreading in mouse brains. J Exp Med. 2021;218(1):e20192193.PubMedCrossRef
135.
Castillo-Carranza DL, Guerrero-Munoz MJ, Sengupta U, Gerson JE, Kayed R. Alpha-synuclein oligomers induce a unique toxic tau strain. Biol Psychiatry. 2018;84(7):499–508.PubMedPubMedCentralCrossRef
136.
Williams T, Sorrentino Z, Weinrich M, Giasson BI, Chakrabarty P. Differential cross-seeding properties of tau and alpha-synuclein in mouse models of tauopathy and synucleinopathy. Brain Commun. 2020;2(2):fcaa090.PubMedPubMedCentralCrossRef
137.
Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R. Alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem. 1999;274(36):25481–9.PubMedCrossRef
138.
Torres-Garcia L, JM PD, Brandi E, Haikal C, Mudannayake JM, Bras IC, et al. Monitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementation. Sci Rep. 2022;12(1):2987.
139.
Gracia P, Polanco D, Tarancon-Diez J, Serra I, Bracci M, Oroz J, et al. Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau. Nat Commun. 2022;13(1):4586.PubMedPubMedCentralCrossRef
140.
Subedi S, Sasidharan S, Nag N, Saudagar P, Tripathi T. Amyloid cross-seeding: mechanism, implication, and inhibition. Molecules. 2022;27(6).
141.
Oki S, Iwashita K, Kimura M, Kano H, Shiraki K. Mechanism of co-aggregation in a protein mixture with small additives. Int J Biol Macromol. 2018;107(Pt B):1428–37.PubMedCrossRef
142.
Sengupta U, Kayed R. Amyloid beta, Tau, and alpha-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases. Prog Neurobiol. 2022;214: 102270.PubMedCrossRef
143.
Sengupta U, Puangmalai N, Bhatt N, Garcia S, Zhao Y, Kayed R. Polymorphic alpha-synuclein strains modified by dopamine and docosahexaenoic acid interact differentially with tau protein. Mol Neurobiol. 2020;57(6):2741–65.PubMedPubMedCentralCrossRef
144.
Hojjatian A, Dasari AKR, Sengupta U, Taylor D, Daneshparvar N, Yeganeh FA, et al. Tau induces formation of alpha-synuclein filaments with distinct molecular conformations. Biochem Biophys Res Commun. 2021;554:145–50.PubMedPubMedCentralCrossRef
145.
Waxman EA, Giasson BI. Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci. 2011;31(21):7604–18.PubMedPubMedCentralCrossRef
146.
Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, et al. Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013;154(1):103–17.PubMedCrossRef
147.
Vacchi E, Kaelin-Lang A, Melli G. Tau and alpha synuclein synergistic effect in neurodegenerative diseases: when the periphery is the core. Int J Mol Sci. 2020;21(14):5030.PubMedPubMedCentralCrossRef
148.
Iwata M, Watanabe S, Yamane A, Miyasaka T, Misonou H. Regulatory mechanisms for the axonal localization of tau protein in neurons. Mol Biol Cell. 2019;30(19):2441–57.PubMedPubMedCentralCrossRef
149.
Praschberger R, Kuenen S, Schoovaerts N, Kaempf N, Singh J, Janssens J, et al. Neuronal identity defines alpha-synuclein and tau toxicity. Neuron. 2023;111(10):1577–9011.PubMedPubMedCentralCrossRef
150.
Henrich MT, Geibl FF, Lakshminarasimhan H, Stegmann A, Giasson BI, Mao X, et al. Determinants of seeding and spreading of alpha-synuclein pathology in the brain. Sci Adv. 2022;6(46):1eabc2487.
151.
Vasili E, Dominguez-Meijide A, Outeiro TF. Spreading of alpha-synuclein and tau: a systematic comparison of the mechanisms involved. Front Mol Neurosci. 2019;12:107.PubMedPubMedCentralCrossRef
152.
Beach TG, Adler CH, Sue LI, Shill HA, Driver-Dunckley E, Mehta SH, et al. Vagus nerve and stomach synucleinopathy in Parkinson’s disease, incidental lewy body disease, and normal elderly subjects: evidence against the “body-first” hypothesis. J Parkinsons Dis. 2021;11(4):1833–43.PubMedPubMedCentralCrossRef
153.
Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010;119(6):689–702.PubMedPubMedCentralCrossRef
154.
Couchie D, Mavilia C, Georgieff IS, Liem RK, Shelanski ML, Nunez J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc Natl Acad Sci U S A. 1992;89(10):4378–81.PubMedPubMedCentralCrossRef
155.
Himmler A, Drechsel D, Kirschner MW, Martin DW Jr. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol. 1989;9(4):1381–8.PubMedPubMedCentral
156.
Derkinderen P, Rolli-Derkinderen M, Chapelet G, Neunlist M, Noble W. Tau in the gut, does it really matter? J Neurochem. 2021;158(2):94–104.PubMedCrossRef
157.
Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206–14.PubMedPubMedCentralCrossRef
158.
Qureshi IA, Tirucherai G, Ahlijanian MK, Kolaitis G, Bechtold C, Grundman M. A randomized, single ascending dose study of intravenous BIIB092 in healthy participants. Alzheimers Dement (N Y). 2018;4:746–55.PubMedCrossRef
159.
Shin J, Kim HJ, Jeon B. Immunotherapy targeting neurodegenerative proteinopathies: alpha-synucleinopathies and tauopathies. J Mov Disord. 2020;13(1):11–9.PubMedCrossRef
160.
Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci. 2014;34(28):9441–54.PubMedPubMedCentralCrossRef
161.
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80(2):402–14.PubMedPubMedCentralCrossRef
162.
Iyer A, Claessens M. Disruptive membrane interactions of alpha-synuclein aggregates. Biochim Biophys Acta Proteins Proteom. 2019;1867(5):468–82.PubMedCrossRef
Metadata
Title
Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration
Authors
Wen Li
Jia-Yi Li
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2024
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-024-00407-y

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