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    Daryl A Bosco PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-603
    Worcester MA 01605
    Phone508-334-3035
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Biography

        Daryl Bosco received her Ph.D. (bio-organic chemistry) in 2003 from Brandeis University, where she used NMR spectroscopy to study enzyme dynamics. From 2003-2005, Dr. Bosco was a post-doctoral fellow in the lab of Jeffery W. Kelly at the Scripps Research Institute, where she studied the effect of oxidative cholesterol metabolites on the mis-folding of alpha-synuclein, a Parkinson's disease-associated protein. Prior to joining the faculty at UMMS in 2008, Dr. Bosco was an Instructor of Neurology at Harvard Medical School and worked on various aspects of ALS in the Cecile B. Day lab directed by Dr. Robert H. Brown, Jr. at the Massachusetts General Hospital.

        Research

        Elucidating the factors involved in sporadic ALS

        photo of Dr. Daryl BoscoOne focus of my lab is to elucidate the molecular mechanism(s) underlying sporadic forms of neurodegenerative diseases, with a focus on amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. Approximately 10% of ALS cases are inherited or familial in nature (FALS), whereas the vast majority (~90%) of cases have an unknown etiology and are thus classified as sporadic ALS (SALS). The factors involved in SALS have yet to be identified; the challenge being that sporadic forms of neurodegenerative diseases are multifactorial, involving a complex interplay between genetics and environment. Our goal is to develop relevant models to identify genetic and environmental factors involved in SALS pathogenesis.

        Investigating the misfolding of SOD1 wild-type in sporadic ALS

        Mutations in the gene encoding Cu, Zn-superoxide dismutase (SOD1) are known to cause FALS. Recently, we found that misfolded forms of the wild-type (WT)-SOD1 protein are associated with SALS, and exert the same toxic effect on axonal transport as FALS-linked mutant SOD1 proteins. We are currently investigating the post-translational modifications of WT-SOD1 that cause it to misfold in vivo, and are developing aberrantly modified WT-SOD1 proteins, such as oxidized SOD1 (SODox), to study in vitro. The properties of these SOD1 proteins are being investigated in the context of various cell biological and biophysical assays.

        Investigating the pathogenic mechanism of FUS/TLS in neurodegeneration

        Genetic variants in the gene encoding FUS/TLS, a nuclear RNA binding protein, have recently been linked to FALS. Moreover, FUS pathology in the form of cytoplasmic aggregates has been detected in a spectrum of neurodegenerative disorders. It is not clear whether FUS pathogenesis stems from a loss of normal nuclear FUS function, or from a gain of toxic function in the cytoplasm, and thus we are exploring both possible mechanisms. We are investigating the pathogenic role of FALS-linked FUS in the following processes i) transcription, ii) axonal transport, and iii) stress-response (e.g., pathways that involve the formation of stress-granules).

        In our lab and in collaboration with others, we employ cell biology, biochemistry, structural biology (e.g., NMR and X-ray crystallography), and mass spectrometry approaches for the investigations described above.



        Rotation Projects

        Rotation Projects:

        1. We recently showed that modified forms of WT-SOD1 mimic FALS-linked mutant SOD1 (Nature Neuroscience, 2010). Next we will investigate the aberrant conformation of modified WT-SOD1 proteins by structural methods. This project entails recombinant protein expression and purification, NMR spectroscopy, X-ray crystallography and mass spectrometry.
        2. We recently found that FALS-linked mutant FUS, but not WT-FUS, incorporates into stress granules (Human Molecular Genetics, 2010). Next we will investigate the role of FUS in stress granule assembly. This project entails cell culture and microscopy.
        3. We are investigating the effect of mutant-FUS on axonal transport. This project entails recombinant protein expression and purification, and cell culture.
        4. Developing new animal models of FUS. This project entails cloning and microscopy.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Sama RR, Ward CL, Kaushansky LJ, Lemay N, Ishigaki S, Urano F, Bosco DA. FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress. J Cell Physiol. 2013 Nov; 228(11):2222-31.
          View in: PubMed
        2. Morfini GA, Bosco DA, Brown H, Gatto R, Kaminska A, Song Y, Molla L, Baker L, Marangoni MN, Berth S, Tavassoli E, Bagnato C, Tiwari A, Hayward LJ, Pigino GF, Watterson DM, Huang CF, Banker G, Brown RH, Brady ST. Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase. PLoS One. 2013; 8(6):e65235.
          View in: PubMed
        3. Broering TJ, Wang H, Boatright NK, Wang Y, Baptista K, Shayan G, Garrity KA, Kayatekin C, Bosco DA, Matthews CR, Ambrosino DM, Xu Z, Babcock GJ. Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1. PLoS One. 2013; 8(4):e61210.
          View in: PubMed
        4. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH, Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 22; 488(7412):499-503.
          View in: PubMed
        5. Guareschi S, Cova E, Cereda C, Ceroni M, Donetti E, Bosco DA, Trotti D, Pasinelli P. An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci U S A. 2012 Mar 27; 109(13):5074-9.
          View in: PubMed
        6. van Blitterswijk M, Gulati S, Smoot E, Jaffa M, Maher N, Hyman BT, Ivinson AJ, Scherzer CR, Schoenfeld DA, Cudkowicz ME, Brown RH, Bosco DA. Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011 Nov; 12(6):430-8.
          View in: PubMed
        7. Bosco DA, Lavoie MJ, Petsko GA, Ringe D. Proteostasis and movement disorders: Parkinson's disease and amyotrophic lateral sclerosis. Cold Spring Harb Perspect Biol. 2011; 3(10).
          View in: PubMed
        8. Ju S, Tardiff DF, Han H, Divya K, Zhong Q, Maquat LE, Bosco DA, Hayward LJ, Brown RH, Lindquist S, Ringe D, Petsko GA. A Yeast Model of FUS/TLS-Dependent Cytotoxicity. PLoS Biol. 2011 Apr; 9(4):e1001052.
          View in: PubMed
        9. Bosco DA, Landers JE. Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets. CNS Neurol Disord Drug Targets. 2010 Dec; 9(6):779-90.
          View in: PubMed
        10. Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P, Goolsby H, Fontaine BA, Lemay N, McKenna-Yasek D, Frosch MP, Agar JN, Julien JP, Brady ST, Brown RH. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010 Nov; 13(11):1396-403.
          View in: PubMed
        11. Bosco DA, Eisenmesser EZ, Clarkson MW, Wolf-Watz M, Labeikovsky W, Millet O, Kern D. Dissecting the microscopic steps of the cyclophilin A enzymatic cycle on the biological HIV-1 capsid substrate by NMR. J Mol Biol. 2010 Nov 12; 403(5):723-38.
          View in: PubMed
        12. Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ, Sapp P, McKenna-Yasek D, Brown RH, Hayward LJ. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet. 2010 Nov 1; 19(21):4160-75.
          View in: PubMed
        13. Ticozzi N, LeClerc AL, Keagle PJ, Glass JD, Wills AM, van Blitterswijk M, Bosco DA, Rodriguez-Leyva I, Gellera C, Ratti A, Taroni F, McKenna-Yasek D, Sapp PC, Silani V, Furlong CE, Brown RH, Landers JE. Paraoxonase gene mutations in amyotrophic lateral sclerosis. Ann Neurol. 2010 Jul; 68(1):102-7.
          View in: PubMed
        14. Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA, Brown RH, Brown H, Tiwari A, Hayward L, Edgar J, Nave KA, Garberrn J, Atagi Y, Song Y, Pigino G, Brady ST. Axonal transport defects in neurodegenerative diseases. J Neurosci. 2009 Oct 14; 29(41):12776-86.
          View in: PubMed
        15. Gao J, Bosco DA, Powers ET, Kelly JW. Localized thermodynamic coupling between hydrogen bonding and microenvironment polarity substantially stabilizes proteins. Nat Struct Mol Biol. 2009 Jul; 16(7):684-90.
          View in: PubMed
        16. Labeikovsky W, Eisenmesser EZ, Bosco DA, Kern D. Structure and dynamics of pin1 during catalysis by NMR. J Mol Biol. 2007 Apr 13; 367(5):1370-81.
          View in: PubMed
        17. Bieschke J, Zhang Q, Bosco DA, Lerner RA, Powers ET, Wentworth P, Kelly JW. Small molecule oxidation products trigger disease-associated protein misfolding. Acc Chem Res. 2006 Sep; 39(9):611-9.
          View in: PubMed
        18. Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P, Lerner RA, Kelly JW. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol. 2006 May; 2(5):249-53.
          View in: PubMed
        19. Eisenmesser EZ, Millet O, Labeikovsky W, Korzhnev DM, Wolf-Watz M, Bosco DA, Skalicky JJ, Kay LE, Kern D. Intrinsic dynamics of an enzyme underlies catalysis. Nature. 2005 Nov 3; 438(7064):117-21.
          View in: PubMed
        20. Bosco DA, Kern D. Catalysis and binding of cyclophilin A with different HIV-1 capsid constructs. Biochemistry. 2004 May 25; 43(20):6110-9.
          View in: PubMed
        21. Bosco DA, Eisenmesser EZ, Pochapsky S, Sundquist WI, Kern D. Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A. Proc Natl Acad Sci U S A. 2002 Apr 16; 99(8):5247-52.
          View in: PubMed
        22. Eisenmesser EZ, Bosco DA, Akke M, Kern D. Enzyme dynamics during catalysis. Science. 2002 Feb 22; 295(5559):1520-3.
          View in: PubMed
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