Biomedical Sciences

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Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis

Received: 10 August 2017    Accepted: 30 August 2017    Published: 12 September 2017
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Abstract

RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.

DOI 10.11648/j.bs.20170304.11
Published in Biomedical Sciences (Volume 3, Issue 4, July 2017)
Page(s) 67-77
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

TLS, FUS, Biotinylated Isoxazole, Biotin-Lys-His, Low Complexity Domain, Amyotrophic Lateral Sclerosis

References
[1] Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208-1211, doi: 323/5918/1208 [pii]10.1126/science.1165942
[2] Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205-1208, doi: 323/5918/1205 [pii]10.1126 /science.1166066.
[3] Mackenzie IR & Neumann M (2016) Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. Journal of neurochemistry 138 Suppl 1, 54-70, doi: 10.1111/jnc.13588.
[4] Ludolph AC, Brettschneider J & Weishaupt JH (2012) Amyotrophic lateral sclerosis. Current opinion in neurology 25, 530-535, doi: 10.1097/WCO.0b013e328356d328.
[5] Arbab M, Baars S & Geijsen N Modeling motor neuron disease: the matter of time. Trends Neurosci 37, 642-652, doi: 10.1016/j.tins.2014.07.008.
[6] Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62, doi: 10.1038/362059a0.
[7] Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, doi: 10.1126/science.1154584.
[8] Lagier-Tourenne C & Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136, 1001-1004, doi: S0092-8674(09)00263-3 [pii]10.1016/j.cell.2009.03.006.
[9] Taylor JP, Brown Jr RH & Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539, 197-206, doi: 10.1038/nature20413.
[10] Kurokawa R (2015) Long Noncoding RNAs. In, pp. 257. Springer.
[11] Lipovich L, Tarca AL, Cai J, Jia H, Chugani HT, Sterner KN, Grossman LI, Uddin M, Hof PR, Sherwood CC, et al. (2014) Developmental changes in the transcriptome of human cerebral cortex tissue: long noncoding RNA transcripts. Cereb Cortex 24, 1451-1459, doi: 10.1093/cercor/bhs414.
[12] Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, et al. (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome research 22, 1775-1789, doi: 10.1101/gr.132159.111.
[13] Carninci P & Kasukawa T & Katayama S & Gough J & Frith MC & Maeda N & Oyama R & Ravasi T & Lenhard B & Wells C, et al. (2005) The transcriptional landscape of the mammalian genome. Science 309, 1559-1563, doi: 309/5740/1559 [pii]10.1126/science.1112014.
[14] Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, et al. (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 106, 11667-11672, doi: 0904715106 [pii]10.1073 /pnas.0904715106.
[15] Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grutzner F & Kaessmann H (2014) The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 505, 635-640, doi: 10.1038/nature12943.
[16] Chi KR (2016) Finding function in mystery transcripts. Nature 529, 423-425, doi: 10.1038/529423a.
[17] Kurokawa R (2012) Generation of Functional Long Noncoding RNA Through Transcription and Natural Selection. In Regulatory RNAs, pp. 151-174. Springer.
[18] Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, et al. (2012) Landscape of transcription in human cells. Nature 489, 101-108, doi: 10.1038/nature11233.
[19] Hon C-C, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJL, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, et al. (2017) An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543, 199-204, doi: 10.1038 /nature21374 http://www.nature.com/nature/journal/v543/n7644/abs/nature21374.html#supplementary-information.
[20] Kurokawa R (2011) Long noncoding RNA as a regulator for transcription. Prog Mol Subcell Biol 51, 29-41, doi: 10.1007/978-3-642-16502-3_2.
[21] Kurokawa R (2011) Promoter-associated long noncoding RNAs repress transcription through a RNA binding protein TLS. Advances in experimental medicine and biology 722, 196-208, doi: 10.1007/978-1-4614-0332-6_12.
[22] Kurokawa R (2015) Initiation of Transcription Generates Divergence of Long Noncoding RNAs. In Long Noncoding RNAs, pp. 69-91. Springer.
[23] Kurokawa R, Rosenfeld MG & Glass CK (2009) Transcriptional regulation through noncoding RNAs and epigenetic modifications. RNA Biol 6, 233-236, doi: 8329 [pii].
[24] Carninci P, Sandelin A, Lenhard B, Katayama S, Shimokawa K, Ponjavic J, Semple CA, Taylor MS, Engstrom PG, Frith MC, et al. (2006) Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 38, 626-635, doi: ng1789 [pii]10.1038/ng1789.
[25] Duret L, Chureau C, Samain S, Weissenbach J & Avner P (2006) The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653-1655, doi: 312/5780/1653 [pii]10.1126/science.1126316.
[26] Johnsson P, Ackley A, Vidarsdottir L, Lui W-O, Corcoran M, Grandér D & Morris KV (2013) A pseudogene long noncoding RNA network regulates PTEN transcription and translation in human cells. Nature structural & molecular biology 20, 440-446, doi: 10.1038/nsmb.2516.
[27] Scarola M, Comisso E, Pascolo R, Chiaradia R, Maria Marion R, Schneider C, Blasco MA, Schoeftner S & Benetti R (2015) Epigenetic silencing of Oct4 by a complex containing SUV39H1 and Oct4 pseudogene lncRNA. Nat Commun 6, 7631, doi: 10.1038/ncomms8631.
[28] Yoneda R, Suzuki S, Mashima T, Kondo K, Nagata T, Katahira M & Kurokawa R (2016) The binding specificity of Translocated in LipoSarcoma/FUsed in Sarcoma with lncRNA transcribed from the promoter region of cyclin D1. Cell & bioscience 6, 4, doi: 10.1186/s13578-016-0068-8.
[29] Wang X, Arai S, Song X, Reichart D, Du K, Pascual G, Tempst P, Rosenfeld MG, Glass CK & Kurokawa R (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126-130, doi: nature06992 [pii]10.1038/nature06992.
[30] Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, et al. (2013) Controversies and priorities in amyotrophic lateral sclerosis. The Lancet Neurology 12, 310-322, doi: 10.1016/S1474-4422(13)70036-X.
[31] Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, et al. (2015) ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron 88, 678-690, doi: 10.1016/j.neuron.2015.10.030.
[32] Lagier-Tourenne C, Polymenidou M & Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19, R46-64, doi: ddq137 [pii]10.1093/hmg/ddq137.
[33] Sun S, Ling S-C, Qiu J, Albuquerque CP, Zhou Y, Tokunaga S, Li H, Qiu H, Bui A, Yeo GW, et al. (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6, doi: 10.1038/ncomms7171.
[34] DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256, doi: 10.1016/j.neuron.2011.09.011.
[35] Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268, doi: 10.1016/j.neuron.2011.09.010.
[36] Jucker M & Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51, doi: 10.1038/nature12481.
[37] Jain A & Vale RD (2017) RNA phase transitions in repeat expansion disorders. Nature 546, 243-247, doi: 10.1038/nature22386.
[38] Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, et al. (2012) Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753-767, doi: 10.1016/j.cell.2012.04.017.
[39] Han TW, Kato M, Xie S, Wu LC, Mirzaei H, Pei J, Chen M, Xie Y, Allen J, Xiao G, et al. (2012) Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768-779, doi: 10.1016/j.cell.2012.04.016.
[40] Kurokawa R & Bando T (2016) Three-Dimensional Structure of RNA-Binding Protein TLS Co-Crystallized with Biotinylated Isoxazole. Biomedical Sciences 2, 1-10, doi: 10.11648/j.rnat.20160201.11.
[41] Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry DJ, Longgood J, Frantz DE, Olson EN, et al. (2008) Cardiogenic small molecules that enhance myocardial repair by stem cells. Proceedings of the National Academy of Sciences 105, 6063-6068, doi: 10.1073/pnas.0711507105.
[42] Song X, Wang X, Arai S & Kurokawa R (2012) Promoter-associated noncoding RNA from the CCND1 promoter. Methods in molecular biology 809, 609-622, doi: 10.1007/978-1-61779-376-9_39.
[43] Asamitsu S, Kawamoto Y, Hashiya F, Hashiya K, Yamamoto M, Kizaki S, Bando T & Sugiyama H (2014) Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole-imidazole polyamide-chlorambucil conjugates targeting CAG/CTG trinucleotide repeats. Bioorg Med Chem 22, 4646-4657, doi: 10.1016/j.bmc.2014.07.019.
[44] Kawamoto Y, Sasaki A, Hashiya K, Ide S, Bando T, Maeshima K & Sugiyama H (2015) Tandem trimer pyrrole-imidazole polyamide probes targeting 18 base pairs in human telomere sequences. Chemical Science 6, 2307-2312, doi: 10.1039/c4sc03755c.
[45] Guex N & Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714-2723, doi: 10.1002/elps.1150181505.
[46] Rahman MM, Kitao S, Tsuji D, Suzuki K, Sakamoto J-I, Matsuoka K, Matsuzawa F, Aikawa S-I & Itoh K (2013) Inhibitory effects and specificity of synthetic sialyldendrimers toward recombinant human cytosolic sialidase 2 (NEU2). Glycobiology 23, 495-504, doi: 10.1093/glycob/cws221.
[47] Berchowitz Luke E, Kabachinski G, Walker Margaret R, Carlile Thomas M, Gilbert Wendy V, Schwartz Thomas U & Amon A (2015) Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis. Cell 163, 406-418, doi: http://dx.doi.org/10.1016/j.cell.2015.08.060.
[48] Schwartz Jacob C, Wang X, Podell Elaine R & Cech Thomas R (2013) RNA Seeds Higher-Order Assembly of FUS Protein. Cell Reports 5, 918-925, doi: http://dx.doi.org/10.1016/j.celrep.2013.11.017.Kurokawa R (2015) Initiation of Transcription Generates Divergence of Long Noncoding RNAs. In Long Noncoding RNAs, pp. 69-91. Springer.
[49] Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, et al. (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467-473, doi: 10.1038/nature11922.
[50] Ling SC, Albuquerque CP, Han JS, Lagier-Tourenne C, Tokunaga S, Zhou H & Cleveland DW (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A 107, 13318-13323, doi: 1008227107 [pii]10.1073 /pnas.1008227107.
[51] Alberti S, Halfmann R, King O, Kapila A & Lindquist S (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137, 146-158, doi: 10.1016/j.cell.2009.02.044.
[52] King OD, Gitler AD & Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Research 1462, 61-80, doi: 10.1016/j.brainres.2012.01.016.
[53] Elbaum-Garfinkle S & Brangwynne CP (2015) Liquids, Fibers, and Gels: The Many Phases of Neurodegeneration. Dev Cell 35, 531-532, doi: 10.1016/j.devcel.2015.11.014.
[54] Hyman AA, Weber CA & Julicher F (2014) Liquid-liquid phase separation in biology. Annu Rev Cell Dev Biol 30, 39-58, doi: 10.1146/annurev-cellbio-100913-013325.
[55] Wojciechowska M & Krzyzosiak WJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Human molecular genetics 20, 3811-3821, doi: 10.1093/hmg/ddr299.
Author Information
  • Division of Gene Structure and Function, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

  • Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan

  • Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan

  • Division of Gene Structure and Function, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

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    Naomi Ueda, Gengo Kashiwazaki, Toshikazu Bando, Riki Kurokawa. (2017). Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomedical Sciences, 3(4), 67-77. https://doi.org/10.11648/j.bs.20170304.11

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    ACS Style

    Naomi Ueda; Gengo Kashiwazaki; Toshikazu Bando; Riki Kurokawa. Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomed. Sci. 2017, 3(4), 67-77. doi: 10.11648/j.bs.20170304.11

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    AMA Style

    Naomi Ueda, Gengo Kashiwazaki, Toshikazu Bando, Riki Kurokawa. Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis. Biomed Sci. 2017;3(4):67-77. doi: 10.11648/j.bs.20170304.11

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  • @article{10.11648/j.bs.20170304.11,
      author = {Naomi Ueda and Gengo Kashiwazaki and Toshikazu Bando and Riki Kurokawa},
      title = {Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis},
      journal = {Biomedical Sciences},
      volume = {3},
      number = {4},
      pages = {67-77},
      doi = {10.11648/j.bs.20170304.11},
      url = {https://doi.org/10.11648/j.bs.20170304.11},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.bs.20170304.11},
      abstract = {RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.},
     year = {2017}
    }
    

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  • TY  - JOUR
    T1  - Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis
    AU  - Naomi Ueda
    AU  - Gengo Kashiwazaki
    AU  - Toshikazu Bando
    AU  - Riki Kurokawa
    Y1  - 2017/09/12
    PY  - 2017
    N1  - https://doi.org/10.11648/j.bs.20170304.11
    DO  - 10.11648/j.bs.20170304.11
    T2  - Biomedical Sciences
    JF  - Biomedical Sciences
    JO  - Biomedical Sciences
    SP  - 67
    EP  - 77
    PB  - Science Publishing Group
    SN  - 2575-3932
    UR  - https://doi.org/10.11648/j.bs.20170304.11
    AB  - RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.
    VL  - 3
    IS  - 4
    ER  - 

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