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Open Access 01-12-2023 | Pathology | Research

Carboxyl truncation of α-synuclein occurs early and is influenced by human APOE genotype in transgenic mouse models of α-synuclein pathogenesis

Authors: Grace M. Lloyd, Brooke Long, Stephan Quintin, Zachary A. Sorrentino, Kimberly-Marie M. Gorion, Brach M. Bell, Denise Carrillo, Patrick Sullivan, David Borchelt, Benoit I. Giasson

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Post-translational modifications to the carboxyl (C) terminus domain of α-synuclein can play an important role in promoting the pathologic aggregation of α-synuclein. Various cleavages that diminish this highly charged, proline-rich region can result in exposure of hydrophobic, aggregation-prone regions, thereby accelerating the aggregation kinetics of α-synuclein into misfolded, pathologic forms. C-terminally truncated forms of α-synuclein are abundant in human diseased brains compared to controls, suggesting a role in disease pathogenesis. Factors that alter the homeostatic proteolytic processing of α-synuclein may ultimately tip the balance towards a progressive disease state. Apolipoprotein E (APOE) has been implicated in the acceleration of cognitive impairment in patients with Lewy body diseases. The APOE4 isoform has been found to cause dysregulation in the endosomal–lysosomal pathway, which could result in altered α-synuclein degradation as a potential mechanism for promoting its pathologic misfolding. Herein, we investigate the spatiotemporal accumulation of C-terminally truncated α-synuclein in a seeded and progressive mouse model of synucleinopathy. Furthermore, we study how this process is influenced in the context of mice that are altered to express either the human APOE3 or APOE4 isoforms. We found that specific C-terminal truncation of α-synuclein occurs at early stages of pathogenesis. We also found that proteolytic processing of this domain differs across various brain regions and is influenced by the presence of different human APOE isoforms. Our data demonstrate an early pathogenic role for C-terminally truncated α-synuclein, and highlight the influence of APOE isoforms in modulating its impact.

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Allen Institute for Brain Science (2004) Interactive Atlas viewer: Atlas viewer. In: Allen mouse brain atlas. Accessed 13 Mar 2023

Bassil F, Fernagut PO, Bezard E, Pruvost A, Leste-Lasserre T, Hoang QQ, Ringe D, Petsko GA, Meissner WG (2016) Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc Natl Acad Sci U S A 113:9593–9598. https://doi.org/10.1073/pnas.1609291113CrossRefPubMedPubMedCentral

Behl T, Kumar S, Althafar ZM, Sehgal A, Singh S, Sharma N, Badavath VN, Yadav S, Bhatia S, Al-Harrasi A, Almoshari Y, Almikhlafi MA, Bungau S (2022) Exploring the role of ubiquitin-proteasome system in Parkinson’s disease. Mol Neurobiol 59:4257–4273. https://doi.org/10.1007/s12035-022-02851-1CrossRefPubMed

Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG, Nalls MA, Clark LN, Honig LS, Marder K, Van Der Flier WM, Lemstra A, Scheltens P, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Ortega-Cubero S, Pastor P, Ferman TJ, Graff-Radford NR, Ross OA, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Compta Y, Revesz T, Lees A, Cairns N, Halliday GM, Mann D, Pickering-Brown S, Dickson DW, Singleton A, Hardy J (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet 23:6139–6146. https://doi.org/10.1093/hmg/ddu334CrossRefPubMedPubMedCentral

Burré J, Sharma M, Südhof TC (2018) Cell biology and pathophysiology of α-synuclein. Cold Spring Harb Perspect Med 8:a024091. https://doi.org/10.1101/cshperspect.a024091CrossRefPubMedPubMedCentral

Chen L, Thiruchelvam MJ, Madura K, Richfield EK (2006) Proteasome dysfunction in aged human α-synuclein transgenic mice. Neurobiol Dis 23:120–126. https://doi.org/10.1016/j.nbd.2006.02.004CrossRefPubMed

Crystal AS, Giasson BI, Crowe A, Kung MP, Zhuang ZP, Trojanowski JQ, Lee VMY (2003) A comparison of amyloid fibrillogenesis using the novel fluorescent compound K114. J Neurochem 86:1359–1368. https://doi.org/10.1046/j.1471-4159.2003.01949.xCrossRefPubMed

Daigle TL, Madisen L, Hage TA, Valley MT, Knoblich U, Larsen RS, Takeno MM, Huang L, Gu H, Larsen R, Mills M, Bosma-Moody A, Siverts LA, Walker M, Graybuck LT, Yao Z, Fong O, Nguyen TN, Garren E, Lenz GH, Chavarha M, Pendergraft J, Harrington J, Hirokawa KE, Harris JA, Nicovich PR, McGraw MJ, Ollerenshaw DR, Smith KA, Baker CA, Ting JT, Sunkin SM, Lecoq J, Lin MZ, Boyden ES, Murphy GJ, da Costa NM, Waters J, Li L, Tasic B, Zeng H (2018) A suite of transgenic driver and reporter mouse lines with enhanced brain-cell-type targeting and functionality. Cell 174:465-480.e22. https://doi.org/10.1016/j.cell.2018.06.035CrossRefPubMedPubMedCentral

Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A, Haines JN, Dhavale DD, Miller R, Choudhury FA, Sullivan PM, Cruchaga C, Perlmutter JS, Ulrich JD, Benitez BA, Kotzbauer PT, Holtzman DM (2020) APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med 12:eaay3069. https://doi.org/10.1126/scitranslmed.aay3069CrossRefPubMedPubMedCentral

10.

Dhillon J-KS, Riffe C, Moore BD, Ran Y, Chakrabarty P, Golde TE, Giasson BI (2017) A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. PLoS ONE 12:e0184731. https://doi.org/10.1371/journal.pone.0184731CrossRefPubMedPubMedCentral

11.

Dickson DW, Heckman MG, Murray ME, Soto AI, Walton RL, Diehl NN, van Gerpen JA, Uitti RJ, Wszolek ZK, Ertekin-Taner N, Knopman DS, Petersen RC, Graff-Radford NR, Boeve BF, Bu G, Ferman TJ, Ross OA (2018) APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91:e1182–e1195. https://doi.org/10.1212/WNL.0000000000006212CrossRefPubMedPubMedCentral

12.

Dikic I (2017) Proteasomal and autophagic degradation systems. Annu Rev Biochem 86:193–224. https://doi.org/10.1146/annurev-biochem-061516-044908CrossRefPubMed

13.

Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB, Gollomp SM, Grossman M, Lee VMY, Trojanowski JQ (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of α-Synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59:830–841. https://doi.org/10.1093/jnen/59.9.830CrossRefPubMed

14.

Gallardo G, Schlüter OM, Südhof TC (2008) A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat Neurosci 11:301–308. https://doi.org/10.1038/nn2058CrossRefPubMed

15.

Giasson BI, Lee VMY (2003) Are ubiquitination pathways central to parkinson’s disease? Cell 114:1–8. https://doi.org/10.1016/S0092-8674(03)00509-9CrossRefPubMed

16.

Goedert M, Jakes R, Spillantini MG (2017) The synucleinopathies: twenty years on. J Parkinsons Dis 7:S51–S69. https://doi.org/10.3233/JPD-179005CrossRefPubMedPubMedCentral

17.

Grassi D, Howard S, Zhou M, Diaz-Perez N, Urban NT, Guerrero-Given D, Kamasawa N, Volpicelli-Daley LA, LoGrasso P, Lasmézas CI (2018) Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc Natl Acad Sci U S A 115:E2634–E2643. https://doi.org/10.1073/pnas.1713849115CrossRefPubMedPubMedCentral

18.

Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, Shepherd CE, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Bras J (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64–74. https://doi.org/10.1016/S1474-4422(17)30400-3CrossRefPubMed

19.

Harris JA, Mihalas S, Hirokawa KE, Whitesell JD, Choi H, Bernard A, Bohn P, Caldejon S, Casal L, Cho A, Feiner A, Feng D, Gaudreault N, Gerfen CR, Graddis N, Groblewski PA, Henry AM, Ho A, Howard R, Knox JE, Kuan L, Kuang X, Lecoq J, Lesnar P, Li Y, Luviano J, McConoughey S, Mortrud MT, Naeemi M, Ng L, Oh SW, Ouellette B, Shen E, Sorensen SA, Wakeman W, Wang Q, Wang Y, Williford A, Phillips JW, Jones AR, Koch C, Zeng H (2019) Hierarchical organization of cortical and thalamic connectivity. Nature 575:195–202. https://doi.org/10.1038/s41586-019-1716-zCrossRefPubMedPubMedCentral

20.

Hass EW, Sorrentino ZA, Xia Y, Lloyd GM, Trojanowski JQ, Prokop S, Giasson BI (2021) Disease-, region- and cell type specific diversity of α-synuclein carboxy terminal truncations in synucleinopathies. Acta Neuropathol Commun 9:146. https://doi.org/10.1186/s40478-021-01242-2CrossRefPubMedPubMedCentral

21.

Huang X, Chen P, Kaufer DI, Tröster AI, Poole C (2006) Apolipoprotein E and dementia in Parkinson disease: A meta-analysis. Arch Neurol 63:189–193CrossRefPubMed

22.

Jin Y, Li F, Sonoustoun B, Kondru NC, Martens YA, Qiao W, Heckman MG, Ikezu TC, Li Z, Burgess JD, Amerna D, O’Leary J, DeTure MA, Zhao J, McLean PJ, Dickson DW, Ross OA, Bu G, Zhao N (2022) APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer’s disease with Lewy body pathology. Acta Neuropathol 143:641–662. https://doi.org/10.1007/s00401-022-02421-8CrossRefPubMedPubMedCentral

23.

Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N (1999) Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103:1579–1586. https://doi.org/10.1172/JCI6172CrossRefPubMedPubMedCentral

24.

Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy Bodies: Dissimilar Incorporation of α-Synuclein, Ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253. https://doi.org/10.1093/jnen/62.12.1241CrossRefPubMed

25.

Lashuel HA, Mahul-Mellier A-L, Novello S, Hegde RN, Jasiqi Y, Altay MF, Donzelli S, DeGuire SM, Burai R, Magalhães P, Chiki A, Ricci J, Boussouf M, Sadek A, Stoops E, Iseli C, Guex N (2022) Revisiting the specificity and ability of phospho-S129 antibodies to capture alpha-synuclein biochemical and pathological diversity. npj Park Dis 8:136. https://doi.org/10.1038/s41531-022-00388-7CrossRef

26.

Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176. https://doi.org/10.1038/nature05453CrossRefPubMed

27.

Liu B, Ruan J, Chen M, Li Z, Manjengwa G, Schlüter D, Song W, Wang X (2022) Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases. Mol Psychiatry 27:259–268. https://doi.org/10.1038/s41380-021-01233-8CrossRefPubMed

28.

Liu CW, Giasson BI, Lewis KA, Lee VM, DeMartino GN, Thomas PJ (2005) A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation: Implications for pathogenesis of parkinson disease. J Biol Chem 280:22670–22678. https://doi.org/10.1074/jbc.M501508200CrossRefPubMed

29.

Lloyd GM, Sorrentino ZA, Quintin S, Gorion K-MM, Bell BM, Paterno G, Long B, Prokop S, Giasson BI (2022) Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice. Acta Neuropathol 143:663–685. https://doi.org/10.1007/s00401-022-02425-4CrossRefPubMedPubMedCentral

30.

Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM, Ritz B, Rausch R, Rhodes SL, Factor SA, Wood-Siverio C, Quinn JF, Chung KA, Peterson AL, Espay AJ, Revilla FJ, Devoto J, Hu SC, Cholerton BA, Wan JY, Montine TJ, Edwards KL, Zabetian CP (2014) APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol 71:1405–1412. https://doi.org/10.1001/jamaneurol.2014.1455CrossRefPubMedCentral

31.

McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O’Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K (2017) Diagnosis and management of dementia with Lewy bodies. Neurology 89:88–100CrossRefPubMedPubMedCentral

32.

Nonaka T, Iwatsubo T, Hasegawa M (2005) Ubiquitination of α-synuclein. Biochemistry 44:361–368. https://doi.org/10.1021/bi0485528CrossRefPubMed

33.

Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, Wang Q, Lau C, Kuan L, Henry AM, Mortrud MT, Ouellette B, Nguyen TN, Sorensen SA, Slaughterbeck CR, Wakeman W, Li Y, Feng D, Ho A, Nicholas E, Hirokawa KE, Bohn P, Joines KM, Peng H, Hawrylycz MJ, Phillips JW, Hohmann JG, Wohnoutka P, Gerfen CR, Koch C, Bernard A, Dang C, Jones AR, Zeng H (2014) A mesoscale connectome of the mouse brain. Nature 508:207–214. https://doi.org/10.1038/nature13186CrossRefPubMedPubMedCentral

34.

Okubadejo NU, Okunoye O, Ojo OO, Arabambi B, Akinyemi RO, Osaigbovo GO, Abubakar SA, Iwuozo EU, Wahab KW, Agabi OP, Agulanna U, Imarhiagbe FA, Abiodun OV, Achoru CO, Adebowale AA, Adeniji O, Akpekpe JE, Ali MW, Ani-Osheku I, Arigbodi O, Balarabe SA, Bello AH, Ekenze OS, Erameh CO, Farombi TH, Fawale MB, Komolafe MA, Nwani PO, Nwazor EO, Nyandaiti Y, Obehighe EE, Obiabo YO, Odeniyi OA, Odiase FE, Ojini FI, Onwuegbuzie GA, Osemwegie N, Oshinaike OO, Otubogun FM, Oyakhire SI, Taiwo FT, Williams UE, Ozomma S, Zubair Y, Hernandez D, Bandres-Ciga S, Blauwendraat C, Singleton A, Houlden H, Hardy J, Rizig M (2022) APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease. npj Park Dis 8:155. https://doi.org/10.1038/s41531-022-00411-xCrossRef

35.

Outeiro TF, Alcalay RN, Antonini A, Attems J, Bonifati V, Cardoso F, Chesselet M-F, Hardy J, Madeo G, McKeith I, Mollenhauer B, Moore DJ, Rascol O, Schlossmacher MG, Soreq H, Stefanis L, Ferreira JJ (2023) Defining the riddle in order to solve it: there is more than one “Parkinson’s disease.” Mov Disord Epub ahead. https://doi.org/10.1002/mds.29419CrossRef

36.

Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, Donaghy P, Morris C, Taylor JP, Thomas A, Attems J, McKeith I (2019) Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14:5. https://doi.org/10.1186/s13024-019-0306-8CrossRefPubMedPubMedCentral

37.

Paul KC, Rausch R, Creek MM, Sinsheimer JS, Bronstein JM, Bordelon Y, Ritz B (2016) APOE, MAPT, and COMT and Parkinson’s disease susceptibility and cognitive symptom progression. J Parkinsons Dis 6:349–359. https://doi.org/10.3233/JPD-150762CrossRefPubMedPubMedCentral

38.

Payami H, Nutt J, Kaye J, Bird T, Camicioli R, Zareparsi S, Sexton G, Swanson P (2002) Age at onset of Parkinson disease and apolipoprotein E genotypes. Am J Med Genet 107:156–161. https://doi.org/10.1002/ajmg.10111CrossRefPubMed

39.

Pu JL, Jin CY, Wang ZX, Fang Y, Li YL, Xue NJ, Zheng R, Lin ZH, Yan YQ, Si XL, Chen Y, Liu Y, Song Z, Yan YP, Tian J, Yin XZ, Zhang BR (2022) Apolipoprotein E genotype contributes to motor progression in Parkinson’s disease. Mov Disord 37:196–200. https://doi.org/10.1002/mds.28805CrossRefPubMed

40.

Quintin S, Lloyd GM, Paterno G, Xia Y, Sorrentino Z, Bell BM, Gorion K-M, Lee EB, Prokop S, Giasson BI (2023) Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114. J Biol Chem 299:104912. https://doi.org/10.1016/j.jbc.2023.104912CrossRefPubMed

41.

Rongve A, Witoelar A, Ruiz A, Athanasiu L, Abdelnour C, Clarimon J, Heilmann-Heimbach S, Hernández I, Moreno-Grau S, de Rojas I, Morenas-Rodríguez E, Fladby T, Sando SB, Bråthen G, Blanc F, Bousiges O, Lemstra AW, van Steenoven I, Londos E, Almdahl IS, Pålhaugen L, Eriksen JA, Djurovic S, Stordal E, Saltvedt I, Ulstein ID, Bettella F, Desikan RS, Idland AV, Toft M, Pihlstrøm L, Snaedal J, Tárraga L, Boada M, Lleó A, Stefánsson H, Stefánsson K, Ramírez A, Aarsland D, Andreassen OA (2019) GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Sci Rep 9:7013. https://doi.org/10.1038/s41598-019-43458-2CrossRefPubMedPubMedCentral

42.

Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW, McGarvey NH, Ayers JI, Notterpek L, Borchelt DR, Golde TE, Giasson BI (2014) Intramuscular injection of -synuclein induces CNS -synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci 111:10732–10737. https://doi.org/10.1073/pnas.1321785111CrossRefPubMedPubMedCentral

43.

Sorrentino ZA, Brooks MMT, Hudson V, Rutherford NJ, Golde TE, Giasson BI, Chakrabarty P (2017) Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity. Mol Neurodegener 12:40. https://doi.org/10.1186/s13024-017-0182-zCrossRefPubMedPubMedCentral

44.

Sorrentino ZA, Giasson BI (2020) The emerging role of α-synuclein truncation in aggregation and disease. J Biol Chem 295:10224–10244. https://doi.org/10.1074/jbc.REV120.011743CrossRefPubMedCentral

45.

Sorrentino ZA, Xia Y, Funk C, Riffe CJ, Rutherford NJ, Ceballos Diaz C, Sacino AN, Price ND, Golde TE, Giasson BI, Chakrabarty P (2018) Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration. Neurobiol Dis 120:98–106. https://doi.org/10.1016/j.nbd.2018.09.005CrossRefPubMedPubMedCentral

46.

Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272:17972–17980. https://doi.org/10.1074/jbc.272.29.17972CrossRefPubMed

47.

Sullivan PM, Mezdour H, Quarfordt SH, Maeda N (1998) Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human APOE*2. J Clin Invest 102:130–135. https://doi.org/10.1172/JCI2673CrossRefPubMedPubMedCentral

48.

Szwedo AA, Dalen I, Pedersen KF, Camacho M, Bäckström D, Forsgren L, Tzoulis C, Winder-Rhodes S, Hudson G, Liu G, Scherzer CR, Lawson RA, Yarnall AJ, Williams-Gray CH, Macleod AD, Counsell CE, Tysnes OB, Alves G, Maple-Grødem J (2022) GBA and APOE Impact cognitive decline in Parkinson’s disease: a 10-year population-based study. Mov Disord 37:1016–1027. https://doi.org/10.1002/mds.28932CrossRefPubMedPubMedCentral

49.

Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP (2013) APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70:223–228. https://doi.org/10.1001/jamaneurol.2013.600CrossRefPubMedPubMedCentral

50.

Waxman EA, Giasson BI (2008) Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein. J Neuropathol Exp Neurol 67:402–416. https://doi.org/10.1097/NEN.0b013e31816fc995CrossRefPubMed

51.

Wilhelmus MMM, Bol JGJM, Van Haastert ES, Rozemuller AJM, Bu G, Drukarch B, Hoozemans JJM (2011) Apolipoprotein e and LRP1 increase early in Parkinson’s disease pathogenesis. Am J Pathol 179:2152–2156. https://doi.org/10.1016/j.ajpath.2011.07.021CrossRefPubMedPubMedCentral

52.

Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, Meneses AD, Li F, Shue F, Zheng J, Van Ingelgom AJ, Davis MD, Kurti A, Knight JA, Linares C, Chen Y, Delenclos M, Liu C-C, Fryer JD, Asmann YW, McLean PJ, Dickson DW, Ross OA, Bu G (2020) APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med 12:eaay1809. https://doi.org/10.1126/scitranslmed.aay1809CrossRefPubMedPubMedCentral

Title: Carboxyl truncation of α-synuclein occurs early and is influenced by human APOE genotype in transgenic mouse models of α-synuclein pathogenesis
Authors: Grace M. Lloyd
Brooke Long
Stephan Quintin
Zachary A. Sorrentino
Kimberly-Marie M. Gorion
Brach M. Bell
Denise Carrillo
Patrick Sullivan
David Borchelt
Benoit I. Giasson
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Pathology
Parkinson's Disease
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01623-9

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Carboxyl truncation of α-synuclein occurs early and is influenced by human APOE genotype in transgenic mouse models of α-synuclein pathogenesis

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Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence

Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease