Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology

  • Mhyre TR, Boyd JT, Hamill RW, Maguire-Zeiss KA. Parkinson’s disease. Subcell Biochem. 2012;65:389–455. https://doi.org/10.1007/978-94-007-5416-4_16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13.

    Article  PubMed  Google Scholar 

  • Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949–53. https://doi.org/10.1126/science.1227157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gómez-Benito M, Granado N, García-Sanz P, Michel A, Dumoulin M, Moratalla R. Modeling Parkinson’s Disease With the Alpha-Synuclein Protein. Front Pharmacol. 2020;11:356. https://doi.org/10.3389/fphar.2020.00356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan OW, Chung KK. The role of alpha-synuclein oligomerization and aggregation in cellular and animal models of Parkinson’s disease. PLoS ONE. 2012;7(6):e38545. https://doi.org/10.1371/journal.pone.0038545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh D, Mehra S, Sahay S, Singh PK, Maji SK. α-synuclein aggregation and its modulation. Int J Biol Macromol. 2017;100:37–54. https://doi.org/10.1016/j.ijbiomac.2016.10.021.

    Article  CAS  PubMed  Google Scholar 

  • Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem. 2002;277(3):1641–4. https://doi.org/10.1074/jbc.C100560200.

    Article  CAS  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3(12):1301–6. https://doi.org/10.1038/81834.

    Article  CAS  PubMed  Google Scholar 

  • Brown TP, Rumsby PC, Capleton AC, Rushton L, Levy LS. Pesticides and Parkinson’s disease–is there a link? Environ Health Perspect. 2006;114(2):156–64. https://doi.org/10.1289/ehp.8095.

    Article  PubMed  Google Scholar 

  • Cascella R, Bigi A, Cremades N, Cecchi C. Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies. Cell Mol Life Sci. 2022;79(3):174. https://doi.org/10.1007/s00018-022-04166-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahul-Mellier AL, Burtscher J, Maharjan N, Weerens L, Croisier M, Kuttler F, Leleu M, Knott GW, Lashuel HA. 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(9):4971–82. https://doi.org/10.1073/pnas.1913904117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayes MT. Parkinson’s Disease and Parkinsonism. Am J Med. 2019;132(7):802–7. https://doi.org/10.1016/j.amjmed.2019.03.001.

    Article  PubMed  Google Scholar 

  • Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020;323(6):548–60. https://doi.org/10.1001/jama.2019.22360.

    Article  PubMed  Google Scholar 

  • Dong J, Cui Y, Li S, Le W. Current pharmaceutical treatments and alternative therapies of Parkinson’s disease. Curr Neuropharmacol. 2016;14(4):339–55. https://doi.org/10.2174/1570159×14666151120123025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie R, Seppi K, Coelho M, Sampaio C, Movement Disorder Society Evidence-Based Medicine Committee. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018;33(8):1248–66. https://doi.org/10.1002/mds.27372.

    Article  CAS  PubMed  Google Scholar 

  • Xilouri M, Brekk OR, Stefanis L. α-Synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol. 2013;47(2):537–51. https://doi.org/10.1007/s12035-012-8341-2.

    Article  CAS  PubMed  Google Scholar 

  • Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M, Koyama S, Kato T. Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J Biol Chem. 2010;285(52):40732–44. https://doi.org/10.1074/jbc.M110.141952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emmanouilidou E, Stefanis L, Vekrellis K. Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging. 2010;31(6):953–68. https://doi.org/10.1016/j.neurobiolaging.2008.07.008.

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Khoshaghideh F, Patel S, Lee SJ. Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004;24(8):1888–96. https://doi.org/10.1523/JNEUROSCI.3809-03.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305(5688):1292–5. https://doi.org/10.1126/science.1101738.

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Investig. 2008;118(2):777–88. https://doi.org/10.1172/JCI32806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe Y, Tatebe H, Taguchi K, Endo Y, Tokuda T, Mizuno T, Nakagawa M, Tanaka M. p62/SQSTM1-dependent autophagy of Lewy body-like α-synuclein inclusions. PLoS ONE. 2012;7(12):e52868. https://doi.org/10.1371/journal.pone.0052868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K. Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy. Acta Neuropathol. 2012;124(2):173–86. https://doi.org/10.1007/s00401-012-0975-7.

    Article  CAS  PubMed  Google Scholar 

  • Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Sharon R, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik KS. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol. 2002;160(5):1655–67. https://doi.org/10.1016/S0002-9440(10)61113-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuusisto E, Parkkinen L, Alafuzoff I. Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol. 2003;62(12):1241–53. https://doi.org/10.1093/jnen/62.12.1241.

    Article  CAS  PubMed  Google Scholar 

  • Bohush A, Niewiadomska G, Weis S, Filipek A. HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson’s Disease and Dementia with Lewy Bodies. J Parkinsons Dis. 2019;9(1):97–107. https://doi.org/10.3233/JPD-181443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao L, Zhao J, Zhong K, Tong A, Jia D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022;7(1):113. https://doi.org/10.1038/s41392-022-00966-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan X, Jin WY, Lu J, Wang J, Wang YT. Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat Neurosci. 2014;17(3):471–80. https://doi.org/10.1038/nn.3637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qu J, Ren X, Xue F, He Y, Zhang R, Zheng Y, Huang H, Wang W, Zhang J. Specific Knockdown of α-Synuclein by Peptide-Directed Proteasome Degradation Rescued Its Associated Neurotoxicity. Cell Chem Biol. 2020;27(6):751-762.e4. https://doi.org/10.1016/j.chembiol.2020.03.010.

    Article  CAS  PubMed  Google Scholar 

  • Kargbo RB. PROTAC Compounds Targeting α-Synuclein Protein for Treating Neurogenerative Disorders: Alzheimer’s and Parkinson’s Diseases. ACS Med Chem Lett. 2020;11(6):1086–7. https://doi.org/10.1021/acsmedchemlett.0c00192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinault MP, Cuendet AF, Mattoo RU, Mensi M, Dietler G, Lashuel HA, Goloubinoff P. Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. J Biol Chem. 2010;285(49):38173–82. https://doi.org/10.1074/jbc.M110.127753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubin DM, Finley D. Proteolysis. The proteasome: a protein-degrading organelle? Curr Biol. 1995;5(8):854–8. https://doi.org/10.1016/s0960-9822(95)00172-2.

    Article  CAS  PubMed  Google Scholar 

  • Sriram SM, Kim BY, Kwon YT. The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat Rev Mol Cell Biol. 2011;12(11):735–47. https://doi.org/10.1038/nrm3217.

    Article  CAS  PubMed  Google Scholar 

  • Kwon YT, Xia Z, Davydov IV, Lecker SH, Varshavsky A. Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3alpha) of the N-end rule pathway. Mol Cell Biol. 2001;21(23):8007–21. https://doi.org/10.1128/MCB.21.23.8007-8021.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tasaki T, Mulder LC, Iwamatsu A, Lee MJ, Davydov IV, Varshavsky A, Muesing M, Kwon YT. A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Mol Cell Biol. 2005;25(16):7120–36. https://doi.org/10.1128/MCB.25.16.7120-7136.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sriram SM, Banerjee R, Kane RS, Kwon YT. Multivalency-assisted control of intracellular signaling pathways: application for ubiquitin- dependent N-end rule pathway. Chem Biol. 2009;16(2):121–31. https://doi.org/10.1016/j.chembiol.2009.01.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cha-Molstad H, Sung KS, Hwang J, Kim KA, Yu JE, Yoo YD, Jang JM, Han DH, Molstad M, Kim JG, Lee YJ, Zakrzewska A, Kim SH, Kim ST, Kim SY, Lee HG, Soung NK, Ahn JS, Ciechanover A, Kim BY, et al. Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding. Nature cell Biol. 2015;17(7):917–29. https://doi.org/10.1038/ncb3177.

    Article  CAS  PubMed  Google Scholar 

  • Cha-Molstad H, Yu JE, Feng Z, Lee SH, Kim JG, Yang P, Han B, Sung KW, Yoo YD, Hwang J, McGuire T, Shim SM, Song HD, Ganipisetti S, Wang N, Jang JM, Lee MJ, Kim SJ, Lee KH, Hong JT, et al. p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat Commun. 2017;8(1):102. https://doi.org/10.1038/s41467-017-00085-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo YD, Mun SR, Ji CH, Sung KW, Kang KY, Heo AJ, Lee SH, An JY, Hwang J, Xie XQ, Ciechanover A, Kim BY, Kwon YT. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. Proc Natl Acad Sci USA. 2018;115(12):E2716–24. https://doi.org/10.1073/pnas.1719110115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji CH, Kim HY, Heo AJ, Lee SH, Lee MJ, Kim SB, Srinivasrao G, Mun SR, Cha-Molstad H, Ciechanover A, Choi CY, Lee HG, Kim BY, Kwon YT. The N-Degron Pathway Mediates ER-phagy. Mol Cell. 2019;75(5):1058-1072.e9. https://doi.org/10.1016/j.molcel.2019.06.028.

    Article  CAS  PubMed  Google Scholar 

  • Shim, S. M., Choi, H. R., Kwon, S. C., Kim, H. Y., Sung, K. W., Jung, E. J., Mun, S. R., Bae, T. H., Kim, D. H., Son, Y. S., Jung, C. H., Lee, J., Lee, M. J., Park, J. W., Kwon, Y. T. The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10. Autophagy. 2022;1–20. https://doi.org/10.1080/15548627.2022.2126617.Advance online publication.

  • Lee YJ, Kim JK, Jung CH, Kim YJ, Jung EJ, Lee SH, Choi HR, Son YS, Shim SM, Jeon SM, Choe JH, Lee SH, Whang J, Sohn KC, Hur GM, Kim HT, Yeom J, Jo EK, Kwon YT. Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria. Autophagy. 2022;18(12):2926–45. https://doi.org/10.1080/15548627.2022.2054240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Mun SR, Linares JF, Ahn J, Towers CG, Ji CH, Fitzwalter BE, Holden MR, Mi W, Shi X, Moscat J, Thorburn A, Diaz-Meco MT, Kwon YT, Kutateladze TG. ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nat Commun. 2018;9(1):4373. https://doi.org/10.1038/s41467-018-06878-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji CH, Kim HY, Lee MJ, Heo AJ, Park DY, Lim S, Shin S, Yang WS, Jung CA, Kim KY, Jeong EH, Park SH, Bin Kim S, Lee SJ, Na JE, Kang JI, Chi HM, Kim HT, Kim YK, Kim BY, et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Commun. 2022;13(1):904. https://doi.org/10.1038/s41467-022-28520-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciechanover A, Kwon YT. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exper Mol Med. 2015;47(3):e147. https://doi.org/10.1038/emm.2014.117.

    Article  CAS  Google Scholar 

  • Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O’Kane CJ, Rubinsztein DC. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol. 2010;190(6):1023–37. https://doi.org/10.1083/jcb.201003122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar S, Olsen AL, Sygnecka K, Lohr KM, Feany MB. α-synuclein impairs autophagosome maturation through abnormal actin stabilization. PLoS Genet. 2021;17(2):e1009359. https://doi.org/10.1371/journal.pgen.1009359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci. 2011;12(8):437–52. https://doi.org/10.1038/nrn3068.

    Article  CAS  PubMed  Google Scholar 

  • Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci USA. 2013;110(19):E1817–26. https://doi.org/10.1073/pnas.1305623110.

    Article  PubMed  PubMed Central  Google Scholar 

  • Deeg AA, Reiner AM, Schmidt F, Schueder F, Ryazanov S, Ruf VC, Giller K, Becker S, Leonov A, Griesinger C, Giese A, Zinth W. Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates. Biochem Biophys Acta. 2015;1850(9):1884–90. https://doi.org/10.1016/j.bbagen.2015.05.021.

    Article  CAS  PubMed  Google Scholar 

  • Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL. The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem. 2004;279(26):26846–57. https://doi.org/10.1074/jbc.M403129200.

    Article  CAS  PubMed  Google Scholar 

  • Javed, H., Ojha, S. Therapeutic Potential of Baicalein in Parkinson’s Disease: Focus on Inhibition of α-Synuclein Oligomerization and Aggregation. In (Ed.), Synucleins – Biochemistry and Role in Diseases. IntechOpen. 2019. https://doi.org/10.5772/intechopen.83589

  • Ahn JS, Lee JH, Kim JH, Paik SR. Novel method for quantitative determination of amyloid fibrils of alpha-synuclein and amyloid beta/A4 protein by using resveratrol. Anal Biochem. 2007;367(2):259–65. https://doi.org/10.1016/j.ab.2007.05.023.

    Article  CAS  PubMed  Google Scholar 

  • Zhang LF, Yu XL, Ji M, Liu SY, Wu XL, Wang YJ, Liu RT. Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T α-synuclein mouse model of Parkinson’s disease. Food Funct. 2018;9(12):6414–26. https://doi.org/10.1039/c8fo00964c.

    Article  CAS  PubMed  Google Scholar 

  • Roy D, Kumar V, James J, Shihabudeen MS, Kulshrestha S, Goel V, Thirumurugan K. Evidence that chemical chaperone 4-Phenylbutyric acid binds to human serum albumin at fatty acid binding sites. PLoS ONE. 2015;10(7):e0133012. https://doi.org/10.1371/journal.pone.0133012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inden M, Kitamura Y, Takeuchi H, Yanagida T, Takata K, Kobayashi Y, Taniguchi T, Yoshimoto K, Kaneko M, Okuma Y, Taira T, Ariga H, Shimohama S. Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone. J Neurochem. 2007;101(6):1491–504. https://doi.org/10.1111/j.1471-4159.2006.04440.x.

    Article  CAS  PubMed  Google Scholar 

  • Burré J, Sharma M, Südhof TC. α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci USA. 2014;111(40):E4274–83. https://doi.org/10.1073/pnas.1416598111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emin D, Zhang YP, Lobanova E, Miller A, Li X, Xia Z, Dakin H, Sideris DI, Lam JYL, Ranasinghe RT, Kouli A, Zhao Y, De S, Knowles TPJ, Vendruscolo M, Ruggeri FS, Aigbirhio FI, Williams-Gray CH, Klenerman D. Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease. Nat Commun. 2022;13(1):5512. https://doi.org/10.1038/s41467-022-33252-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA. 1998;95(11):6469–73. https://doi.org/10.1073/pnas.95.11.6469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L. alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004;279(45):46915–20. https://doi.org/10.1074/jbc.M405146200.

    Article  CAS  PubMed  Google Scholar 

  • Bae EJ, Lee HJ, Lee SJ. Cell models to study cell-to-cell transmission of α-synuclein. Methods Mol Biol. 2016;1345:291–8. https://doi.org/10.1007/978-1-4939-2978-8_19.

    Article  CAS  PubMed  Google Scholar 

  • Lee SJ, Desplats P, Sigurdson C, Tsigelny I, Masliah E. Cell-to-cell transmission of non-prion protein aggregates. Nat Rev Neurol. 2010;6(12):702–6. https://doi.org/10.1038/nrneurol.2010.145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006;281(40):29739–52. https://doi.org/10.1074/jbc.M600933200.

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160–4. https://doi.org/10.1038/ncb748.

    Article  CAS  PubMed  Google Scholar 

  • Yoon YS, You JS, Kim TK, Ahn WJ, Kim MJ, Son KH, Ricarte D, Ortiz D, Lee SJ, Lee HJ. Senescence and impaired DNA damage responses in alpha-synucleinopathy models. Exp Mol Med. 2022;54(2):115–28. https://doi.org/10.1038/s12276-022-00727-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mashimo M, Onishi M, Uno A, Tanimichi A, Nobeyama A, Mori M, Yamada S, Negi S, Bu X, Kato J, Moss J, Sanada N, Kizu R, Fujii T. The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis. J Biol Chem. 2021;296:100046. https://doi.org/10.1074/jbc.RA120.014479.

    Article  CAS  PubMed  Google Scholar 

  • Ganjam GK, Bolte K, Matschke LA, Neitemeier S, Dolga AM, Höllerhage M, Höglinger GU, Adamczyk A, Decher N, Oertel WH, Culmsee C. Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons. Cell Death Dis. 2019;10(11):865. https://doi.org/10.1038/s41419-019-2091-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HJ, Kim C, Lee SJ. Alpha-synuclein stimulation of astrocytes: Potential role for neuroinflammation and neuroprotection. Oxid Med Cell Longev. 2010;3(4):283–7. https://doi.org/10.4161/oxim.3.4.12809.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lei Z, Cao G, Wei G. A30P mutant α-synuclein impairs autophagic flux by inactivating JNK signaling to enhance ZKSCAN3 activity in midbrain dopaminergic neurons. Cell Death Dis. 2019;10(2):133. https://doi.org/10.1038/s41419-019-1364-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi I, Zhang Y, Seegobin SP, Pruvost M, Wang Q, Purtell K, Zhang B, Yue Z. Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun. 2020;11(1):1386. https://doi.org/10.1038/s41467-020-15119-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010;285(12):9262–72. https://doi.org/10.1074/jbc.M109.081125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007;282(8):5641–52. https://doi.org/10.1074/jbc.M609532200.

    Article  CAS  PubMed  Google Scholar 

  • Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 2009;16(1):46–56. https://doi.org/10.1038/cdd.2008.110.

    Article  CAS  PubMed  Google Scholar 

  • Gao J, Perera G, Bhadbhade M, Halliday GM, Dzamko N. Autophagy activation promotes clearance of α-synuclein inclusions in fibril-seeded human neural cells. J Biol Chem. 2019;294(39):14241–56. https://doi.org/10.1074/jbc.RA119.008733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci. 2010;30(3):1166–75. https://doi.org/10.1523/JNEUROSCI.3944-09.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaub T, Gürgen D, Maus D, Lange C, Tarabykin V, Dragun D, Hegner B. mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells. Sci Rep. 2019;9(1):20071. https://doi.org/10.1038/s41598-019-56237-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaldirim M, Lang A, Pfeiler S, Fiegenbaum P, Kelm M, Bönner F, Gerdes N. Modulation of mTOR signaling in cardiovascular disease to target acute and chronic inflammation. Front Cardiovasc Med. 2022;9:907348. https://doi.org/10.3389/fcvm.2022.907348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rusmini P, Cortese K, Crippa V, Cristofani R, Cicardi ME, Ferrari V, Vezzoli G, Tedesco B, Meroni M, Messi E, Piccolella M, Galbiati M, Garrè M, Morelli E, Vaccari T, Poletti A. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019;15(4):631–51. https://doi.org/10.1080/15548627.2018.1535292.

    Article  CAS  PubMed  Google Scholar 

  • Redmann M, Wani WY, Volpicelli-Daley L, Darley-Usmar V, Zhang J. Trehalose does not improve neuronal survival on exposure to alpha-synuclein pre-formed fibrils. Redox Biol. 2017;11:429–37. https://doi.org/10.1016/j.redox.2016.12.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turco E, Witt M, Abert C, Bock-Bierbaum T, Su MY, Trapannone R, Sztacho M, Danieli A, Shi X, Zaffagnini G, Gamper A, Schuschnig M, Fracchiolla D, Bernklau D, Romanov J, Hartl M, Hurley JH, Daumke O, Martens S. FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Mol Cell. 2019;74(2):330-346.e11. https://doi.org/10.1016/j.molcel.2019.01.035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turco E, Savova A, Gere F, Ferrari L, Romanov J, Schuschnig M, Martens S. Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation. Nat Commun. 2021;12(1):5212. https://doi.org/10.1038/s41467-021-25572-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci USA. 2016;113(7):1931–6. https://doi.org/10.1073/pnas.1520335113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan B, Li J, Parajuli N, Tian Z, Wu P, Lewno MT, Zou J, Wang W, Bedford L, Mayer RJ, Fang J, Liu J, Cui T, Su H, Wang X. The Calcineurin-TFEB-p62 pathway mediates the activation of cardiac macroautophagy by proteasomal malfunction. Circ Res. 2020;127(4):502–18. https://doi.org/10.1161/CIRCRESAHA.119.316007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindersson E, Beedholm R, Højrup P, Moos T, Gai W, Hendil KB, Jensen PH. Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem. 2004;279(13):12924–34. https://doi.org/10.1074/jbc.M306390200.

    Article  CAS  PubMed  Google Scholar 

  • Dorsey ER, Sherer T, Okun MS, Bloem BR. The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis. 2018;8(s1):S3–8. https://doi.org/10.3233/JPD-181474.

    Article  PubMed  PubMed Central  Google Scholar 

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