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Research Articles

Dynamic reversibility of α-synuclein serine-129 phosphorylation is impaired in synucleinopathy models. Ramalingam N, Brontesi L, Jin SX, Selkoe DJ, Dettmer U. EMBO Rep. 2023 Oct 23:e57145. doi: 10.15252/embr.202357145. Online ahead of print. PMID: 37870370

Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation. Ramirez E, Ganegamage SK, Min S, Patel H, Ogunware A, Plascencia-Villa G, Alnakhala H, Shimanaka K, Tripathi A, Wang KW, Zhu X, Rochet JC, Kuo MH, Counts SE, Perry G, Dettmer U, Lasagna-Reeves CA, Fortin JS. ACS Chem Neurosci. 2023 Oct 11. doi: 10.1021/acschemneuro.3c00464. Online ahead of print. PMID: 37818657

Discovery of 4-aminoindole carboxamide derivatives to curtail alpha-synuclein and tau isoform 2N4R oligomer formation. Ramirez E, Min S, Ganegamage SK, Shimanaka K, Sosa MG, Dettmer U, Rochet JC, Fortin JS.Results Chem. 2023 Jan;5:100938. doi: 10.1016/j.rechem.2023.100938. Epub 2023 Apr 28.PMID: 37346091 Free PMC article.

5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation. Ramirez E, Ganegamage SK, Elbatrawy AA, Alnakhala H, Shimanaka K, Tripathi A, Min S, Rochet JC, Dettmer U, Fortin JS. ACS Omega. 2023 May 23;8(22):20102-20115. doi: 10.1021/acsomega.3c02668. eCollection 2023 Jun 6. PMID: 37305264 Free PMC article.

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity. Ramalingam N, Jin SX, Moors TE, Fonseca-Ornelas L, Shimanaka K, Lei S, Cam HP, Watson AH, Brontesi L, Ding L, Hacibaloglu DY, Jiang H, Choi SJ, Kanter E, Liu L, Bartels T, Nuber S, Sulzer D, Mosharov EV, Chen WV, Li S, Selkoe DJ, Dettmer U. NPJ Parkinsons Dis. 2023 Jan 16;9(1):4. doi: 10.1038/s41531-023-00444-w.PMID: 36646701 Free PMC article.

The effects of KTKEGV repeat motif and intervening ATVA sequence on α-synuclein solubility and assembly. Brontesi L, Imberdis T, Ramalingam N, Dettmer U. J Neurochem. 2023 Apr;165(2):246-258. doi: 10.1111/jnc.15763. Epub 2023 Jan 28.PMID: 36625497

Anti-fibrillization effects of sulfonamide derivatives on α-synuclein and hyperphosphorylated tau isoform 1N4R. Fortin JS, Shimanaka K, Saraswati AP, Liu M, Wang KW, Hagar HT, Maity S, Ganegamage SK, Ellsworth E, Counts SE, Borhan B, Dettmer U, Kuo MH. J Mol Struct. 2022 Nov 5;1267:133574. doi: 10.1016/j.molstruc.2022.133574. Epub 2022 Jun 23. PMID: 36310922

Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons. Fonseca-Ornelas L, Stricker JMS, Soriano-Cruz S, Weykopf B, Dettmer U, Muratore CR, Scherzer CR, Selkoe DJ. NPJ Parkinsons Dis. 2022 Sep 16;8(1):118. doi: 10.1038/s41531-022-00380-1. PMID: 36114228

Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy. Fanning S, Cirka H, Thies JL, Jeong J, Niemi SM, Yoon J, Ho GPH, Pacheco JA, Dettmer U, Liu L, Clish CB, Hodgetts KJ, Hutchinson JN, Muratore CR, Caldwell GA, Caldwell KA, Selkoe D. NPJ Parkinsons Dis. 2022 Jun 9;8(1):74. doi: 10.1038/s41531-022-00335-6. PMID: 35680956

A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity. Nuber S, Chung CY, Tardiff DF, Bechade PA, McCaffery TD, Shimanaka K, Choi J, Chang B, Raja W, Neves E, Burke C, Jiang X, Xu P, Khurana V, Dettmer U, Fanning S, Rhodes KJ, Selkoe DJ, Scannevin RH. Neurotherapeutics. 2022 Apr;19(3):1018-1036. doi: 10.1007/s13311-022-01199-7. Epub 2022 Apr 20. PMID: 35445353

Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations. de Boni L, Watson AH, Zaccagnini L, Wallis A, Zhelcheska K, Kim N, Sanderson J, Jiang H, Martin E, Cantlon A, Rovere M, Liu L, Sylvester M, Lashley T, Dettmer U, Jaunmuktane Z, Bartels T. Acta Neuropathol. 2022 Apr;143(4):453-469. doi: 10.1007/s00401-022-02406-7. Epub 2022 Feb 9. PMID: 35141810

Pathogenic Mechanisms of Cytosolic and Membrane-Enriched α-Synuclein Converge on Fatty Acid Homeostasis. Tripathi A, Alnakhala H, Terry-Kantor E, Newman A, Liu L, Imberdis T, Fanning S, Nuber S, Ramalingam N, Selkoe D, Dettmer U. J Neurosci. 2022 Mar 9;42(10):2116-2130. doi: 10.1523/JNEUROSCI.1881-21.2022. Epub 2022 Jan 27. PMID: 35086904

Excess membrane binding of monomeric alpha-, beta- and gamma-synuclein is invariably associated with inclusion formation and toxicity. Kim TE, Newman AJ, Imberdis T, Brontesi L, Tripathi A, Ramalingam N, Fanning S, Selkoe D, Dettmer U. Hum Mol Genet. 2021 Nov 16;30(23):2332-2346. doi: 10.1093/hmg/ddab188. PMID: 34254125

Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice. Glajch KE, Moors TE, Chen Y, Bechade PA, Nam AY, Rajsombath MM, McCaffery TD, Dettmer U, Weihofen A, Hirst WD, Selkoe DJ, Nuber S. Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2103425118. doi: 10.1073/pnas.2103425118.

Excess membrane binding of monomeric alpha-, beta- and gamma-synuclein is invariably associated with inclusion formation and toxicity. Kim TE, Newman AJ, Imberdis T, Brontesi L, Tripathi A, Ramalingam N, Fanning S, Selkoe D, Dettmer U. Hum Mol Genet. 2021 Nov 16;30(23):2332-2346. doi: 10.1093/hmg/ddab188.

Crowded organelles, lipid accumulation, and abnormal membrane tubulation in cellular models of enhanced α-synuclein membrane interaction. Ericsson M, von Saucken V, Newman AJ, Doehr L, Hoesch C, Kim TE, Dettmer U. Brain Res. 2021 May 1;1758:147349. doi: 10.1016/j.brainres.2021.147349.

Temperature is a key determinant of alpha- and beta-synuclein membrane interactions in neurons. Ramalingam N, Dettmer U. J Biol Chem. 2021 Jan 8;296:100271. doi: 10.1016/j.jbc.2021.100271.

Upregulation of Cellular Palmitoylation Mitigates α-Synuclein Accumulation and Neurotoxicity. Ho GPH, Ramalingam N, Imberdis T, Wilkie EC, Dettmer U, Selkoe DJ. Mov Disord. 2021 Feb;36(2):348-359. doi: 10.1002/mds.28346.

A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice. Nuber S, Nam AY, Rajsombath MM, Cirka H, Hronowski X, Wang J, Hodgetts K, Kalinichenko LS, Müller CP, Lambrecht V, Winkler J, Weihofen A, Imberdis T, Dettmer U, Fanning S, Selkoe DJ. Ann Neurol. 2021 Jan;89(1):74-90. doi: 10.1002/ana.25920.

Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor. Terry-Kantor E, Tripathi A, Imberdis T, LaVoie ZM, Ho GPH, Selkoe D, Fanning S, Ramalingam N, Dettmer U. Int J Mol Sci. 2020 Jul 22;21(15):5193. doi: 10.3390/ijms21155193.

Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Imberdis T, Negri J, Ramalingam N, Terry-Kantor E, Ho G, Fanning S, Stirtz G, Levy O, Young-Pearse T, Selkoe D, Dettmer U. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20760-20769.  doi: 10.1073/pnas.1903216116.

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Fanning S, Haque A, Imberdis T, Baru V, Barrasa MI, Nuber S, Termine D, Ramalingam N, Ho GPH, Noble T, Sandoe J, Lou Y, Landgraf D, Freyzon Y, Newby G, Soldner F, Terry-Kantor E, Kim TE, Hofbauer HF, Becuwe M, Jaenisch R, Pincus D, Clish CB, Walther TC, Farese RV Jr, Srinivasan S, Welte MA, Kohlwein SD, Dettmer U*, Lindquist S, Selkoe D*.  Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. doi: 10.1016/j.molcel.2018.11.028. (* corresponding authors)

Studying α-Synuclein Conformation by Intact-Cell Cross-Linking. Imberdis T, Fanning S, Newman A, Ramalingam N, Dettmer U*. Methods Mol Biol. 2019;1948:77-91. doi: 10.1007/978-1-4939-9124-2_8.

Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease. Nuber S, Rajsombath M, Minakaki G, Winkler J, Müller CP, Ericsson M, Caldarone B, Dettmer U, Selkoe DJ. Neuron. 2018 Oct 10;100(1):75-90.e5. doi: 10.1016/j.neuron.2018.09.014.

Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form. Collier TJ, Srivastava KR, Justman C, Grammatopoulous T, Hutter-Paier B, Prokesch M, Havas D, Rochet JC, Liu F, Jock K, de Oliveira P, Stirtz GL, Dettmer U, Sortwell CE, Feany MB, Lansbury P, Lapidus L, Paumier KL. Neurobiol Dis. 2017 Oct;106:191-204. doi: 10.1016/j.nbd.2017.07.007.

Loss of native α-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. Dettmer U*, Ramalingam N, von Saucken VE, Kim TE, Newman AJ, Terry-Kantor E, Nuber S, Ericsson M, Fanning S, Bartels T, Lindquist S, Levy OA, Selkoe D. Hum Mol Genet. 2017 Sep 15;26(18):3466-3481. doi: 10.1093/hmg/ddx227. (* corresponding author)

KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity. Dettmer U, Newman AJ, von Saucken VE Bartels T, Selkoe D. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9596-601. doi: 10.1073/pnas.1505953112.

Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, von Saucken VE, Sanderson JB, Jaenisch R, Bartels T, Selkoe D. Nat Commun. 2015 Jun 16;6:7314. doi: 10.1038/ncomms8314.

Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Luth ES, Bartels T, Dettmer U, Kim NC, Selkoe D. Biochemistry. 2015 Jan 20;54(2):279-92. doi: 10.1021/bi501188a.

A New Method for Quantitative Immunoblotting of Endogenous α-Synuclein. Newman AJ, Selkoe D, Dettmer U: PLoS One. 2013 Nov 20;8(11):e81314. doi: 10.1371/journal.pone.0081314

In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. Dettmer U, Newman AJ, Luth ES, Bartels T, Selkoe D: J Biol Chem. 2013 Mar 1;288(9):6371-85. doi: 10.1074/jbc.M112.403311.

The Transmembrane Protein 147 (TMEM147) is a Component of the Nicalin-NOMO Protein Complex. Dettmer U, Kuhn PH, Abou-Ajram C, Lichtenthaler SF, Krüger M, Kremmer E, Haass C, Haffner C. J Biol Chem. 2010 Aug 20;285(34):26174-81. doi: 10.1074/jbc.M110.132548.

The Nicastrin-like protein Nicalin regulates assembly and stability of the Nicalin-nodal modulator (NOMO) membrane protein complex. Haffner C, Dettmer U, Weiler T, Haass C. J Biol Chem. 2007 Apr 6;282(14):10632-8.

 

 

Reviews/Commentaries

 

Astrocytes in Parkinson’s Disease: From Role to Possible Intervention. Wang T, Sun Y, Dettmer U. Cells. 2023 Sep 22;12(19):2336. doi: 10.3390/cells12192336. PMID: 37830550 Free PMC article. Review.

Lipotoxicity Downstream of α-Synuclein Imbalance: A Relevant Pathomechanism in Synucleinopathies? Tripathi A, Fanning S, Dettmer U. Biomolecules. 2021 Dec 28;12(1):40. doi: 10.3390/biom12010040. PMID: 35053188  Review.

Vesicle trafficking and lipid metabolism in synucleinopathy. Fanning S, Selkoe D, Dettmer U. Acta Neuropathol. 2021 Apr;141(4):491-510. doi: 10.1007/s00401-020-02177-z. Epub 2020 Jun 30.PMID: 32607605 Review.

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk. Kayed R, Dettmer U, Lesné SE. J Parkinsons Dis. 2020;10(3):791-818. doi: 10.3233/JPD-201965.PMID: 32508330 Free PMC article. Review.

Parkinson’s disease: proteinopathy or lipidopathy? Fanning S, Selkoe D, Dettmer U. NPJ Parkinsons Dis. 2020 Jan 3;6:3. doi: 10.1038/s41531-019-0103-7. eCollection 2020.PMID: 31909184 Free PMC article. Review.

Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration. Yeboah F, Kim TE, Bill A, Dettmer U. Neurobiol Dis. 2019 Jul 24;132:104543. doi: 10.1016/j.nbd.2019.104543. [Epub ahead of print] Review.

Rationally Designed Variants of α-Synuclein Illuminate Its in vivo Structural Properties in Health and Disease. Dettmer U. Front Neurosci. 2018 Sep 25;12:623. doi: 10.3389/fnins.2018.00623. eCollection 2018. Review.

New insights into cellular α-synuclein homeostasis in health and disease. Dettmer U, Selkoe D, Bartels T. Curr Opin Neurobiol. 2016 Feb;36:15-22. doi: 10.1016/j.conb.2015.07.007

ExPLAining early synucleinopathies. Dettmer U, Bartels T. Brain. 2015 Jun;138(Pt 6):1449-51. doi: 10.1093/brain/awv099

Defining the native state of α-synuclein. Selkoe D, Dettmer U, Luth E, Kim N, Newman AJ, Bartels T. Neurodegener Diseases. 2013 Oct 30; 13(2-3):114-7. doi: 10.1159/000355516.

 

 

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