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6. Weak effects of prebiotically plausible peptides on self-triphosphorylation ribozyme function.

Author

Arriola, Joshua, Poordian, Shayan, Valdivia, Estefanía, Le, Tommy, Leman, Luke, Schellinger, Joan, and Müller, Ulrich

Abstract

Catalytic RNAs (ribozymes) were central to early stages of life on earth. The first ribozymes probably emerged in the presence of prebiotically generated peptides because amino acids can be generated under abiotic conditions, and amino acids can oligomerize into peptides under prebiotically plausible conditions. Here we tested whether the presence of prebiotically plausible peptides could have aided the emergence of ribozymes, by an in vitro selection of self-triphosphorylation ribozymes from random sequence in the presence of ten different octapeptides. These peptides were composed of ten different, prebiotically plausible amino acids, each as mixture of d- and l-stereoisomers. After five rounds of selection and high throughput sequencing analysis, ten ribozymes that appeared most promising for peptide benefits were tested biochemically for possible benefits from each of the ten peptides. The strongest peptide benefit enhanced ribozyme activity by 2.6-fold, similar to the effect from an increase in the pH by one-half unit. Four arbitrarily chosen ribozymes from a previous selection without peptides showed no significant change in their activity in the presence of the ten peptides. Therefore, the used prebiotically plausible peptides - peptides without evolutionarily optimized sequence, without cationic or aromatic side chains - did not provide a strong benefit for the emergence of ribozyme activity. This finding stands in contrast to previously identified polycationic peptides, conjugates between peptides and polyaromatic hydrocarbons, and modern mRNA encoded proteins, all of which can strongly increase ribozyme function. The results are discussed in the context of origins of life.

Published
2024

9. Author Correction: Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Farrell, Kurt, Humphrey, Jack, Chang, Timothy, Zhao, Yi, Leung, Yuk Yee, Kuksa, Pavel P., Patil, Vishakha, Lee, Wan-Ping, Kuzma, Amanda B., Valladares, Otto, Cantwell, Laura B., Wang, Hui, Ravi, Ashvin, De Sanctis, Claudia, Han, Natalia, Christie, Thomas D., Afzal, Robina, Kandoi, Shrishtee, Whitney, Kristen, Krassner, Margaret M., Ressler, Hadley, Kim, SoongHo, Dangoor, Diana, Iida, Megan A., Casella, Alicia, Walker, Ruth H., Nirenberg, Melissa J., Renton, Alan E., Babrowicz, Bergan, Coppola, Giovanni, Raj, Towfique, Höglinger, Günter U., Müller, Ulrich, Golbe, Lawrence I., Morris, Huw R., Hardy, John, Revesz, Tamas, Warner, Tom T., Jaunmuktane, Zane, Mok, Kin Y., Rademakers, Rosa, Dickson, Dennis W., Ross, Owen A., Wang, Li-San, Goate, Alison, Schellenberg, Gerard, Geschwind, Daniel H., Crary, John F., and Naj, Adam

Published
2024
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10. Correction: Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S., Dombroski, Beth A., Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C., Dopper, Elise, Ghetti, Bernardino F., Newell, Kathy L., Troakes, Claire, de Yébenes, Justo G., Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H., Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G., Serrano, Geidy E., Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A., Galasko, Douglas, Boxer, Adam L., Miller, Bruce L., Seeley, Willian W., Van Deerlin, Vivanna M., Lee, Edward B., White, III, Charles L., Morris, Huw, de Silva, Rohan, Crary, John F., Goate, Alison M., Friedman, Jeffrey S., Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C., Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W., Höglinger, Günter U., Schellenberg, Gerard D., Geschwind, Daniel H., and Lee, Wan-Ping

Published
2024
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12. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Author

Farrell, Kurt, Humphrey, Jack, Chang, Timothy, Zhao, Yi, Leung, Yuk Yee, Kuksa, Pavel P., Patil, Vishakha, Lee, Wan-Ping, Kuzma, Amanda B., Valladares, Otto, Cantwell, Laura B., Wang, Hui, Ravi, Ashvin, De Sanctis, Claudia, Han, Natalia, Christie, Thomas D., Afzal, Robina, Kandoi, Shrishtee, Whitney, Kristen, Krassner, Margaret M., Ressler, Hadley, Kim, SoongHo, Dangoor, Diana, Iida, Megan A., Casella, Alicia, Walker, Ruth H., Nirenberg, Melissa J., Renton, Alan E., Babrowicz, Bergan, Coppola, Giovanni, Raj, Towfique, Höglinger, Günter U., Müller, Ulrich, Golbe, Lawrence I., Morris, Huw R., Hardy, John, Revesz, Tamas, Warner, Tom T., Jaunmuktane, Zane, Mok, Kin Y., Rademakers, Rosa, Dickson, Dennis W., Ross, Owen A., Wang, Li-San, Goate, Alison, Schellenberg, Gerard, Geschwind, Daniel H., Crary, John F., and Naj, Adam

Published
2024
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13. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

Author

Wang, Hui, Chang, Timothy S., Dombroski, Beth A., Cheng, Po-Liang, Patil, Vishakha, Valiente-Banuet, Leopoldo, Farrell, Kurt, Mclean, Catriona, Molina-Porcel, Laura, Rajput, Alex, De Deyn, Peter Paul, Le Bastard, Nathalie, Gearing, Marla, Kaat, Laura Donker, Van Swieten, John C., Dopper, Elise, Ghetti, Bernardino F., Newell, Kathy L., Troakes, Claire, de Yébenes, Justo G., Rábano-Gutierrez, Alberto, Meller, Tina, Oertel, Wolfgang H., Respondek, Gesine, Stamelou, Maria, Arzberger, Thomas, Roeber, Sigrun, Müller, Ulrich, Hopfner, Franziska, Pastor, Pau, Brice, Alexis, Durr, Alexandra, Le Ber, Isabelle, Beach, Thomas G., Serrano, Geidy E., Hazrati, Lili-Naz, Litvan, Irene, Rademakers, Rosa, Ross, Owen A., Galasko, Douglas, Boxer, Adam L., Miller, Bruce L., Seeley, Willian W., Van Deerlin, Vivanna M., Lee, Edward B., White, III, Charles L., Morris, Huw, de Silva, Rohan, Crary, John F., Goate, Alison M., Friedman, Jeffrey S., Leung, Yuk Yee, Coppola, Giovanni, Naj, Adam C., Wang, Li-San, Dalgard, Clifton, Dickson, Dennis W., Höglinger, Günter U., Schellenberg, Gerard D., Geschwind, Daniel H., and Lee, Wan-Ping

Published
2024
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15. Peptide conjugates with polyaromatic hydrocarbons can benefit the activity of catalytic RNAs.

Author

Sweeney, Kevin, Le, Tommy, Jorge, Micaella, Schellinger, Joan, Leman, Luke, and Müller, Ulrich

Abstract

Early stages of life likely employed catalytic RNAs (ribozymes) in many functions that are today filled by proteins. However, the earliest life forms must have emerged from heterogenous chemical mixtures, which included amino acids, short peptides, and many other compounds. Here we explored whether the presence of short peptides can help the emergence of catalytic RNAs. To do this, we conducted an in vitro selection for catalytic RNAs from randomized sequence in the presence of ten different peptides with a prebiotically plausible length of eight amino acids. This in vitro selection generated dozens of ribozymes, one of them with ∼900-fold higher activity in the presence of one specific peptide. Unexpectedly, the beneficial peptide had retained its N-terminal Fmoc protection group, and this group was required to benefit ribozyme activity. The same, or higher benefit resulted from peptide conjugates with prebiotically plausible polyaromatic hydrocarbons (PAHs) such as fluorene and naphthalene. This shows that PAH-peptide conjugates can act as potent cofactors to enhance ribozyme activity. The results are discussed in the context of the origin of life.

Published
2023

16. A ribozyme that uses lanthanides as cofactor

Author

Sweeney, Kevin J, Han, Xu, and Müller, Ulrich F

Subjects
Inorganic Chemistry, Chemical Sciences, Biological Sciences, Genetics, RNA, Catalytic, Magnesium, Lanthanoid Series Elements, RNA, Catalysis, Nucleic Acid Conformation, Environmental Sciences, Information and Computing Sciences, Developmental Biology, Biological sciences, Chemical sciences, Environmental sciences
Abstract

To explore how an early, RNA-based life form could have functioned, in vitro selection experiments have been used to develop catalytic RNAs (ribozymes) with relevant functions. We previously identified ribozymes that use the prebiotically plausible energy source cyclic trimetaphosphate (cTmp) to convert their 5'-hydroxyl group to a 5'-triphosphate. While these ribozymes were developed in the presence of Mg2+, we tested here whether lanthanides could also serve as catalytic cofactors because lanthanides are ideal catalytic cations for this reaction. After an in vitro selection in the presence of Yb3+, several active sequences were isolated, and the most active RNA was analyzed in more detail. This ribozyme required lanthanides for activity, with highest activity at a 10:1 molar ratio of cTmp : Yb3+. Only the four heaviest lanthanides gave detectable signals, indicating a high sensitivity of ribozyme catalysis to the lanthanide ion radius. Potassium and Magnesium did not facilitate catalysis alone but they increased the lanthanide-mediated kOBS by at least 100-fold, with both K+ and Mg2+ modulating the ribozyme's secondary structure. Together, these findings show that RNA is able to use the unique properties of lanthanides as catalytic cofactor. The results are discussed in the context of early life forms.

Published
2023

19. Comprehensive evidence implies a higher social cost of CO2

Author

Rennert, Kevin, Errickson, Frank, Prest, Brian C, Rennels, Lisa, Newell, Richard G, Pizer, William, Kingdon, Cora, Wingenroth, Jordan, Cooke, Roger, Parthum, Bryan, Smith, David, Cromar, Kevin, Diaz, Delavane, Moore, Frances C, Müller, Ulrich K, Plevin, Richard J, Raftery, Adrian E, Ševčíková, Hana, Sheets, Hannah, Stock, James H, Tan, Tammy, Watson, Mark, Wong, Tony E, and Anthoff, David

Subjects
Behavioral and Social Science, Basic Behavioral and Social Science, Climate Action, Carbon Dioxide, Climate, Greenhouse Gases, Socioeconomic Factors, Climate Models, Uncertainty, Delay Discounting, Risk, Policy Making, Environmental Policy, General Science & Technology
Abstract

The social cost of carbon dioxide (SC-CO2) measures the monetized value of the damages to society caused by an incremental metric tonne of CO2 emissions and is a key metric informing climate policy. Used by governments and other decision-makers in benefit-cost analysis for over a decade, SC-CO2 estimates draw on climate science, economics, demography and other disciplines. However, a 2017 report by the US National Academies of Sciences, Engineering, and Medicine1 (NASEM) highlighted that current SC-CO2 estimates no longer reflect the latest research. The report provided a series of recommendations for improving the scientific basis, transparency and uncertainty characterization of SC-CO2 estimates. Here we show that improved probabilistic socioeconomic projections, climate models, damage functions, and discounting methods that collectively reflect theoretically consistent valuation of risk, substantially increase estimates of the SC-CO2. Our preferred mean SC-CO2 estimate is $185 per tonne of CO2 ($44-$413 per tCO2: 5%-95% range, 2020 US dollars) at a near-term risk-free discount rate of 2%, a value 3.6 times higher than the US government's current value of $51 per tCO2. Our estimates incorporate updated scientific understanding throughout all components of SC-CO2 estimation in the new open-source Greenhouse Gas Impact Value Estimator (GIVE) model, in a manner fully responsive to the near-term NASEM recommendations. Our higher SC-CO2 values, compared with estimates currently used in policy evaluation, substantially increase the estimated benefits of greenhouse gas mitigation and thereby increase the expected net benefits of more stringent climate policies.

Published
2022

20. Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Author

Hopfner, Franziska, Tietz, Anja, Ruf, Viktoria, Ross, Owen, Koga, Shunsuke, Dickson, Dennis, Aguzzi, Adriano, Attems, Johannes, Beach, Thomas, Beller, Allison, Cheshire, William, van Deerlin, Vivianna, Deuschl, Günther, Duyckaerts, Charles, Ellinghaus, David, Evsyukov, Valentin, Flanagan, Margaret, Franke, Andre, Frosch, Matthew, Gearing, Marla, Gelpi, Ellen, van Gerpen, Jay, Ghetti, Bernardino, Glass, Jonathan, Halliday, Glenda, Helbig, Ingo, Höllerhage, Matthias, Huitinga, Inge, Irwin, David, Keene, Dirk, Kovacs, Gabor, Lee, Edward, Levin, Johannes, Martí, Maria, Mackenzie, Ian, McKeith, Ian, Mclean, Catriona, Mollenhauer, Brit, Neumann, Manuela, Newell, Kathy, Pantelyat, Alex, Pendziwiat, Manuela, Peters, Annette, Molina Porcel, Laura, Rabano, Alberto, Matěj, Radoslav, Rajput, Alex, Rajput, Ali, Reimann, Regina, Scott, William, Selvackadunco, Sashika, Simuni, Tanya, Stadelmann, Christine, Svenningsson, Per, Thomas, Alan, Trenkwalder, Claudia, Troakes, Claire, Trojanowski, John, Uitti, Ryan, White, Charles, Wszolek, Zbigniew, Xie, Tao, Ximelis, Teresa, Yebenes, Justo, Müller, Ulrich, Schellenberg, Gerard, Herms, Jochen, Kuhlenbäumer, Gregor, Höglinger, Günter, Grinberg, Lea, Seeley, William, and Desplats, Paula

Subjects
ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy, Autoantibodies, Autopsy, Genome-Wide Association Study, Humans, Multiple System Atrophy, Nerve Tissue Proteins, Olivopontocerebellar Atrophies, Striatonigral Degeneration, Transcription Factors, alpha-Synuclein
Abstract

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

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