Nancy Bonini

Nancy M. Bonini
Born1959 (age 64–65)[4]
NationalityAmerican
Alma materPrinceton University (AB)

University of Wisconsin-Madison (PhD)

California Institute of Technology (Postdoc)
Known forDeveloped the first Drosophila model of human neurodenerative disease
SpouseAnthony Cashmore
Awards
Scientific career
Fields
InstitutionsUniversity of Pennsylvania
Doctoral advisorDavid L. Nelson
Websitehttp://web.sas.upenn.edu/bonini-lab/

Nancy M. Bonini (born 1959) is an American neuroscientist and geneticist, best known for pioneering the use of Drosophila as a model organism to study neurodegeneration of the human brain. Using the Drosophila model approach, Bonini's laboratory has identified genes and pathways that are important in the development and progression of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's Disease),[5] Alzheimer's disease,[6] and Parkinson's disease,[7][8] as well as aging, neural injury and regeneration,[9] and response to environmental toxins.[8]

A professor of biology at the University of Pennsylvania since 1994, Bonini has held appointments as the inaugural Lucille B. Williams Term Professor of Biology (2006–2012),[10] an Investigator of the Howard Hughes Medical Institute (2000–2013),[1][11] and the Florence RC Murray Professor of Biology (since 2012).[12] She was editor of the Annual Review of Genetics from 2018-2021.[13][14]

Early life and education

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Bonini was born in 1959 to parents Rose and William “Bill” Bonini.[4] Her father was a Professor of GeoScience and Civil Engineering at Princeton University from 1952 to 1996.[15] Nancy, her sister (Jennifer), brothers (Jack and Jamie), and father all attended Princeton University.[16]

Bonini earned an AB degree from Princeton University in 1981, studying Biology.[17] Her undergraduate thesis research, performed under the direction of William (Chip) Quinn, formed the basis for her first publication, "Reward Learning in Normal and Mutant Drosophila".[18] After graduation, Bonini entered the Neurosciences Training Program at the University of Wisconsin–Madison. There, she completed doctoral research in the laboratory of David L. Nelson,[19] graduating with a Doctorate (Ph.D.) in Neuroscience in 1987.[20] Bonini's post-doctoral research was performed in the laboratory of Seymour Benzer (behavioral geneticist) at the California Institute of Technology.[17] Focusing on using the fruit fly as a tool for understanding the genetic basis of the brain and behavior, Bonini was the first to demonstrate that Drosophila can be used as a model of human neurodegenerative disease.[21][22]

Research

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The fruit fly as a model for human neurodegenerative disease

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In 1998, Bonini's research conclusively demonstrated that Drosophila could be used as an in vivo model for human neurodegenerative disease.[21][22] Using this model, Bonini's research group subsequently discovered unexpected and novel pathways that play a role in normal biology, injury, and disease.[17] In the pioneering study that showed that the fruit fly can be used as a model of disease, Bonini's laboratory collaborated with human geneticists to examine the effects of expressing normal and mutant forms of a human neurodegenerative polyQ disease protein. Flies that expressed the mutant form of the protein showed symptoms and characteristics similar to those seen in human polyQ disease patients; flies that expressed the normal protein did not.[23][24]

Chaperones and Polyglutamine Repeat Diseases

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Studying Polyglutamine repeat diseases (polyQ diseases) in Drosophila neurodegeneration models, Bonini's research group elucidated an important role for molecular chaperones in polyQ diseases,[25] and subsequently Parkinson's disease.[7][23][26] In those studies, upregulation of the chaperone Hsp70 suppressed neurodegeneration, and this finding established chaperones as a new therapeutic target for Parkinson's disease and other neurodegenerative disorders.[7][26][27] Bonini's research team demonstrated the pharmacologic potential of chaperones in further Drosophila studies; administering geldanamycin (an antitumor antibiotic that acts on Hsp90) to mutant flies before symptoms of neural decline were visible averted the onset of neurodegeneration in the mutant flies, suggesting a new approach for people susceptible to Parkinson's disease and other neurodegenerative conditions.[28]

Amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease)

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Bonini's research laboratory developed and validated a Drosophila model for familial ALS,[9][29][30] then used an ALS model to evaluate genes and pathways important for ALS onset, progression, and possible treatment.[31][32] Through these studies, Bonini's team, in collaboration with Aaron Gitler, discovered that ATXN2 (the gene that encodes the protein Ataxin-2) was a disease susceptibility gene for ALS, and that interrupting the interaction between TDP-43 and Ataxin-2 was a promising target for treating ALS and other diseases.[30][31][32][33][34]

A role for brain microRNAs in aging and disease

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The Bonini lab discovered that a conserved microRNA, miR-34, plays a neuroprotective role in the brains of aging Drosophila.[35] The loss of miR-34 resulted in a profile consistent with accelerated aging, late-onset brain neurodegeneration, and reduced survival, whereas upregulation of miR-34 enhanced survival and mitigated neurodegeneration.[35][36]

An epigenetic basis for Alzheimer's disease

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In 2018, Bonini, with collaborators Shelley Berger, Brad Johnson, and others, completed a study investigating the epigenetic landscape of tissue samples donated by individuals who did and did not have Alzheimer's disease. The findings established the basis for an epigenetic link between aging and Alzheimer's disease, suggesting a new model for the disease and a paradigm shift from the previously established view of Alzheimer's disease as an 'advanced state of normal aging'. Based on the study findings, Bonini and collaborators established that a set of normal aging changes that occur in the epigenome protect against Alzheimer's disease, and that disrupting those normal protective changes may be a trigger that predisposes people to the disease.[6][37]

Honors and awards

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A professor of biology at the University of Pennsylvania since 1994, Bonini has held appointments as the inaugural Lucille B. Williams Term Professor of Biology (2006–2012),[10] an Investigator of the Howard Hughes Medical Institute (2000–2013),[1][11] and the Florence RC Murray Professor of Biology (2012-).[12] In 2012, she was elected to the National Academy of Sciences,[11][38] and the National Academy of Medicine.[2] Also in 2012, Bonini became an elected Fellow of the American Association for the Advancement of Science.[39] In 2014, Bonini was elected to the American Academy of Arts and Sciences.[3]

Bonini was the recipient of a March of Dimes Basil O'Connor Award in 1996,[40] a Packard Fellowship for Science and Engineering in 1997,[41] an Ellison Medical Foundation Senior Scholar in Aging Research Award in 2009,[42] a Glenn Award for Research in the Biological Mechanisms of Aging in 2015,[43] and a National Institutes of Health Outstanding Investigator R35 Award in 2016.[44][45] In 2010, she appeared as a panelist on Charlie Rose’s The Brain Series (Episode: The Disordered Brain).[46]

Personal

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A.Cashmore

Bonini is married to Anthony Cashmore,[16] a University of Pennsylvania Professor Emeritus best known for discovering the cryptochrome that serves as a blue light photoreceptor in Arabidopsis.[47]

Representative publications

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Journal articles

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  • Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, Bonini NM (1998) Expanded Polyglutamine Protein Forms Nuclear Inclusions and Causes Neural Degeneration in Drosophila. Cell 93(6): 939–949. PMID 9635424.
  • Warrick JM, Chan HY, Gray-Board GL, Paulson H, Bonini NM (1999) Suppression of polyglutamine disease in Drosophila by the molecular chaperone hsp70. Nature Genetics 23: 425–428. PMID 10581028.
  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556):865-8. PMID 11823645
  • Watson MR, Lagow RD, Xu K, Zhang B, Bonini NM (2008) A Drosophila Model for Amyotrophic Lateral Sclerosis Reveals Motor Neuron Damage by Human SOD1. Journal of Biological Chemistry 283:24972-24981. PMID 18596033. (highlighted as paper of the week)[29]
  • Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S, Gitler AD, Bonini NM (2014) Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nature Genetics 46:152-160. PMID 24336168.
  • Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ, Gregory BD, Torres C, Trojanowski JQ, Wang LS, Johnson FB, Bonini NM, Berger SL (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease. Nature Neuroscience 21: 497–505. PMID 29507413.

Reviews

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Commentary

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  • Bonini NM, Hardiman O (2015) Ataxin-2 expands insight into the ALS clinical spectrum. Neurology 84: 244–5. PMID 25527266.
  • Bonini NM, Berger SL (2017) The Sustained Impact of Model Organisms–in Genetics & Epigenetics. Genetics 205:1-4. PMID 28049700.

References

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  1. ^ a b c "Our Investigators: Nancy M. Bonini, PhD". hhmi.org. Howard Hughes Medical Institute. 2019. Retrieved 15 Jul 2019.
  2. ^ a b "ASBMB Today" (PDF). USA: American Society for Biochemistry and Molecular Biology. 1 Dec 2012. Retrieved 15 Jul 2019.
  3. ^ a b "Ellison Medical Foundation Senior Scholar Nancy Bonini elected to American Academy of Arts and Sciences". ellisonfoundation.org. 2014. Retrieved 15 Jul 2019.
  4. ^ a b "Members of the American Academy Listed by election year, 2000–2018" (PDF). amacad.org. American Academy of Arts and Sciences. 2019. Retrieved 1 Aug 2019.
  5. ^ "DC: New ALS Genetics Hog the Limelight at Satellite Conference". www.alzforum.org. FBRI LLC. 2011. Retrieved 21 Jul 2019.
  6. ^ a b "Penn Study Shows that the "Epigenetic Landscape" is Protective in Normal Aging, Impaired in Alzheimer's Disease". Penn Medicine News. USA. 5 Mar 2018. Retrieved 19 Jul 2019.
  7. ^ a b c Whitworth, Alexander; Wes, Paul D.; Pallanck, Leo J. (2006). "Drosophila models pioneer a new approach to drug discovery for Parkinson's disease" (PDF). Drug Discovery Today. 11 (3/4): 119–. doi:10.1016/S1359-6446(05)03693-7. PMID 16533709. Retrieved 20 Jul 2019.
  8. ^ a b "Drosophila Define DJ-1's Defensive Role". www.alzforum.org. FBRI LLC. 16 Dec 2005. Retrieved 21 Jul 2019.
  9. ^ a b Ugur, Berrack; Chen, Kuchuan; Bellen, Hugo J. (2016). "Drosophila tools and assays for the study of human diseases". Disease Models and Mechanisms. 9 (3): 235–244. doi:10.1242/dmm.023762. PMC 4833332. PMID 26935102. Retrieved 21 Jul 2019. The recently developed Drosophila wing injury assay is an elegant approach to study axonal degeneration and regeneration in vivo (Fang et al., 2012). The goal of these studies is to identify genes that are required for axonal degeneration and regeneration, and to identify the regulatory processes that are involved in spinal cord and nerve injuries.
  10. ^ a b "Science Professors to Four Chairs" (PDF). www.almanac.upenn.edu. University of Pennsylvania. 1 May 2007. Retrieved 20 Jul 2019.
  11. ^ a b c "HHMI Scientists Elected to National Academy of Sciences in 2012". www.hhmi.org. Howard Hughes Medical Institute. 1 May 2012.
  12. ^ a b "Dr. Nancy Bonini appointed as the Florence R.C. Murray Professor of Biology". www.bio.upenn.edu. University of Pennsylvania. 8 Aug 2012. Retrieved 20 Jul 2019.
  13. ^ "EDITOR OF THE ANNUAL REVIEW OF GENETICS - VOLUME 52, 2018". Annual Reviews. Retrieved 29 July 2021.
  14. ^ "EDITOR OF THE ANNUAL REVIEW OF GENETICS - VOLUME 55, 2021". Annual Reviews. Retrieved 9 February 2022.
  15. ^ Kelly, Morgan (3 Jan 2017). "Geoscientist William Bonini, dedicated teacher and genial colleague, dies at 90". Princeton University News. Princeton, NJ, USA. Retrieved 12 Jul 2019.
  16. ^ a b "William E. "Bill" Bonini, 90". www.centraljersey.com. Packet Media, LLC. 29 Dec 2016. Retrieved 12 Jul 2019.
  17. ^ a b c Nichols, Peter (1999). "A fly like thee. Studying the fruit fly, Nancy Bonini '81 unravels causes of neurodegenerative diseases". www.princeton.edu. Princeton University. Retrieved 18 Jul 2019.
  18. ^ Tempel, Bruce L.; Bonini, Nancy; Dawson, Douglas R.; Quinn, William G. (1983). "Reward learning in normal and mutant Drosophila". Proceedings of the National Academy of Sciences of the United States of America. 80 (5): 1482–1486. Bibcode:1983PNAS...80.1482T. doi:10.1073/pnas.80.5.1482. PMC 393622. PMID 6572401.
  19. ^ "From the Labs: Dave Nelson Lab" (PDF). University of Wisconsin-Madison Biochemistry Newsletter. Wisconsin, USA. 2010. Retrieved 11 Aug 2019.
  20. ^ "Neuroscience Training Program – Alumni". www.ntp.neuroscience.wisc.edu. University of Wisconsin – Madison. 2019. Retrieved 18 Jul 2019.
  21. ^ a b Warrick, John M; Paulson, Henry L; Gray-Board, Gladys; Fischbeck, Kenneth H; Pittman, Randall N; Bonini, Nancy M. (12 Jun 1998). "Expanded Polyglutamine Protein Forms Nuclear Inclusions and Causes Neural Degeneration in Drosophila". Cell. 93 (6): 939–949. doi:10.1016/S0092-8674(00)81200-3. PMID 9635424. S2CID 17720790.
  22. ^ a b Max Perutz (1 Feb 1999). "Glutamine repeats and neurodegenerative diseases: molecular aspects". Trends in Biochemical Sciences. 24 (2): 58–63. doi:10.1016/S0968-0004(98)01350-4. PMID 10098399.
  23. ^ a b R. Horowski; Y. Mizuno; C.W. Olanow; W. Poewe; P. Riederer; J.A. Stoessel; M.B.H. Youdim (24 July 2003). Advances in Research on Neurodegeneration. Springer Science & Business Media. pp. 52–. ISBN 978-3-211-83907-2. Retrieved 20 July 2019.
  24. ^ Warrick, JM; Chan, HY; Gray-Board, GL; Paulson, H; Bonini, NM (1999). "Suppression of polyglutamine disease in Drosophila by the molecular chaperone hsp70". Nature Genetics. 23 (4): 425–428. doi:10.1038/70532. PMID 10581028. S2CID 24632055.
  25. ^ Chai, Y; Koppenhafer, SL; Bonini, NM; Paulson, HL (1 Dec 1999). "Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease". The Journal of Neuroscience. 19 (23): 10338–47. doi:10.1523/JNEUROSCI.19-23-10338.1999. PMC 6782415. PMID 10575031.
  26. ^ a b Helfand, Stephen L. (1 Feb 2002). "Chaperones Take Flight". Science. 295 (5556): 809–810. doi:10.1126/science.1069544. PMID 11823628. S2CID 84002211.
  27. ^ R. Horowski; Y. Mizuno; C.W. Olanow; W. Poewe; P. Riederer; J.A. Stoessel; M.B.H. Youdim (24 July 2003). "General Aspects of Neurodegeration". Advances in Research on Neurodegeneration. Springer Science & Business Media. p. 117. ISBN 978-3-211-83907-2. Retrieved 20 July 2019.
  28. ^ "Drug Averts Parkinson's Disease in Fruit Flies, Suggesting New Approaches to Human Neurodegenerative Diseases". www.penntoday.upenn.edu. University of Pennsylvania. 11 Nov 2002. Retrieved 22 Jul 2019.
  29. ^ a b "A Fly Model for ALS". Journal of Biological Chemistry. 283: e99948. 5 Sep 2008. doi:10.1016/S0021-9258(19)49256-9.
  30. ^ a b Varslag, Brian (Feb 2011). "Hope Floats: With a new arsenal of robust models of ALS, drug development may move to the fast track". www.hhmi.org. Howard Hughes Medical Institute. Retrieved 21 Jul 2019. In 1998, however, Bonini authored an idea that radically extended the scientific reach of the humble insect. She mused that inserting genes related to human brain diseases might yield critical insights into poorly understood neurodegenerative conditions, including Huntington's disease, Parkinson's disease, and ALS. "I saw it as, 'there are all these terrible diseases and nobody is really studying them in model organisms,'" Bonini says. "I knew it was a high-risk thing."
  31. ^ a b Flam, Faye (26 Aug 2010). "Researchers at University of Pennsylvania find possible genetic link to Lou Gehrig's disease". The Philadelphia Inquirer. Retrieved 16 Jul 2019.
  32. ^ a b Elden, Andrew C.; Kim, Hyung-Jun; Hart, Michael P.; Chen-Plotkin, Alice S.; Johnson, Brian S.; Fang, Xiaodong; Armakola, Maria; Geser, Felix; Greene, Robert; Lu, Min Min; Padmanabhan, Arun; Clay-Falcone, Dana; McCluskey, Leo; Elman, Lauren; Juhr, Denise; Gruber, Peter J.; Rüb, Udo; Auburger, Georg; Trojanowski, John Q.; Lee, Virginia M.-Y.; Van Deerlin, Vivianna M.; Bonini, Nancy M.; Gitler, Aaron D. (2010). "Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS". Nature. 466 (7310): 1069–1078. Bibcode:2010Natur.466.1069E. doi:10.1038/nature09320. PMC 2965417. PMID 20740007.
  33. ^ USA US20110142789A1, Aaron D. Gitler & Nancy M. Bonini, "Compositions and Methods for the Diagnosis and Treatment of Amyotrophic Lateral Sclerosis", assigned to University of Pennsylvania 
  34. ^ Clotilde Lagier-Tourenne; Don W. Cleveland (25 Aug 2010). "An expansion in ALS genetics". Nature. 466 (7310): 1052–1053. doi:10.1038/4661052a. PMID 20740002. S2CID 205056924. "… present evidence on page 1069 of this issue that short expansions of glutamine (Q) amino-acid residues — a polyglutamine, or polyQ tract — in the ataxin-2 protein are associated with increased risk of ALS. This unexpected finding comes 15 years after the discovery that long polyQ expansions in ataxin-2 cause spinocerebellar ataxia type 2, a neurodegenerative disorder involving abnormalities of gait.
  35. ^ a b Aw, Sherry; Cohen, Stephen M. (Aug 2012). "Time is of the essence: microRNAs and age-associated neurodegeneration". Nature. 22 (8): 1218–1220. doi:10.1038/cr.2012.59. PMC 3411169. PMID 22491478.
  36. ^ Gwyneth Dickey Zakaib (17 Feb 2012). "Neurodegeneration and Aging: Could MicroRNA Be the Link?". www.alzforum.org. Retrieved 21 Feb 2019.
  37. ^ Nativio, Raffaella; Donahue, Greg; Berson, Amit; Lan, Yemin; Amlie-Wolf, Alexandre; Tuzer, Ferit; Toledo, Jon B.; Gosai, Sager J.; Gregory, Brian D.; Torres, Claudio; Trojanowski, John Q.; Wang, Li-San; Johnson, F.Brad; Bonini, nancy M.; Berger, Shelley L. (2018). "Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease". Nature Neuroscience. 21 (4): 497–505. doi:10.1038/s41593-018-0101-9. PMC 6124498. PMID 29507413.
  38. ^ "National Academy of Sciences Members and Foreign Associates Elected". www.nasonline.org. National Academy of Sciences. 1 May 2012. Retrieved 20 Jul 2019.
  39. ^ "AAAS Members Elected as Fellows". aaas.org. American Association for the Advancement of Science. Dec 2011. Retrieved 20 Jul 2019.
  40. ^ Bui, Q. T.; Zimmerman, J. E.; Liu, H.; Bonini, N. M. (2000). "Molecular Analysis of Drosophila eyes absent Mutants Reveals Features of the Conserved Eya Domain". Genetics. 155 (2): 709–720. doi:10.1093/genetics/155.2.709. PMC 1461105. PMID 10835393. Retrieved 26 Jul 2019.
  41. ^ "Nancy M. Bonini, 1997 Fellow". www.packard.org. David and Lucile Packard Foundation. 2019. Retrieved 26 Jul 2019.
  42. ^ "2009 Senior Scholar Award in Aging". www.ellisonfoundation.org. Ellison Medical Foundation. 2009. Retrieved 20 Jul 2019.
  43. ^ "Glenn Foundation for Medical Research: Award Recipients". www.glennfoundation.org. Glen Foundation. 2019. Retrieved 20 Jul 2019.
  44. ^ "NINDS Research Program Award (R35) Recipients FY 2017". www.ninds.nih.gov. National Institutes of Health. 28 Jun 2018. Archived from the original on 21 March 2019. Retrieved 20 Jul 2019.
  45. ^ "NIH initiates pilot grant program for innovative neurological research". www.nih.gov. National Institutes of Health. 26 Jan 2017. Retrieved 20 Jul 2019.
  46. ^ Charlie Rose (talk show), Eric Kandel, John Donoghue (neuroscientist), John Krakauer, Nancy Bonini (22 Jul 2010). The Disordered Brain (video). Retrieved 21 Jul 2019. As part of Charlie's Brain Series, a panel of experts gives insight into disorders of the brain, such as Parkinson's disease, stroke, and paralysis, and describes the latest cutting-edge treatments.
  47. ^ Nair, Prashant (11 Jan 2011). "Profile of Anthony R. Cashmore". Proceedings of the National Academy of Sciences. 108 (2): 443–445. Bibcode:2011PNAS..108..443N. doi:10.1073/pnas.1018069108. PMC 3021040. PMID 21191100.
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