Anne Bertolotti

Last updated
Anne Bertolotti
Alma materUniversity of Strasbourg, France
AwardsEMBO Young Investigator (2004)

EMBO member (2013) British Society for Cell Biology Hooke Medal (2014) Fellow of the UK Academy of Medical Sciences (2017)

Biochemical Society GlaxoSmithKline Award (2017)

Contents

Scientific career
FieldsBiochemistry

Cell Biology

Neuroscience
InstitutionsIGBMC

Skirball Institute of Biomolecular Medicine in the New York University School of Medicine Ecole Normale Superieure, Paris France Inserm

MRC Laboratory of Molecular Biology
Website https://www2.mrc-lmb.cam.ac.uk/group-leaders/a-to-g/anne-bertolotti/

Anne Bertolotti FMedSci [1] is a French biochemist and cell biologist who works as Programme Leader at the MRC Laboratory of Molecular Biology (MRC LMB) in Cambridge, UK. [2] In 2022 she was appointed Head of the MRC LMB's Neurobiology Division. [3] She is known for her research into the cellular defences against misfolded proteins and the mechanisms underlying their deposition, the molecular problem causative of neurodegenerative diseases. [1] [4]

Education

Anne Bertolotti earned 2 B.S. degrees in biochemistry and plant physiology and an M.S. degree in cell and molecular biology from the Louis Pasteur University of Strasbourg, France. Bertolotti also received her PhD from the Louis Pasteur University for the discovery of hTAFII68 (now TAF15) while working with Laszlo Tora and Pierre Chambon at Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC). [5]

Academic career

Bertolotti did her post-doctoral research with David Ron at the Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States, making seminal discoveries in the mammalian unfolded protein response. [5] [6] [7] [8]

In 2001, Bertolotti became an Inserm Associate Professor at Ecole Normale Superieure, Paris. [9] In 2006, she became a group leader at the MRC Laboratory of Molecular Biology. [5]

Bertolotti's research focuses on protein quality control systems in cells, due to their importance as the cellular defence against the misfolded proteins that accumulate in degenerative diseases, such as Alzheimer's, Parkinson's or Huntington's disease. [4] [10] She is known for her work on the mechanisms governing aggregation of disease-causing proteins, [11] [12] [13] [14] [15] [16] for identifying components of cellular defense mechanisms against protein aggregation [17] [18] [19] and for the discovery of strategies to rescue cell survival under protein misfolding stress. [20] [21] [22] [23]

One of such strategies consists of selective inhibition of an eIF2 phosphatase to reduce transient protein synthesis, allowing the cell to "catch up" with the required handling of misfolded proteins. [20] [24] Her group subsequently demonstrated that selective inhibitors had therapeutic effects in mouse models of Charcot-Marie-Tooth disease and Huntington's disease. [21] [23] [24]

One of the inhibitors discovered in Bertolotti's lab, Sephin1, has passed through favourable Phase 1 clinical trials in 2019 and is being developed for Charcot-Marie-Tooth disease. [25]

Professional associations and awards

Related Research Articles

<span class="mw-page-title-main">Protein folding</span> Change of a linear protein chain to a 3D structure

Protein folding is the physical process by which a protein, after synthesis by a ribosome as a linear chain of amino acids, changes from an unstable random coil into a more ordered three-dimensional structure. This structure permits the protein to become biologically functional.

<span class="mw-page-title-main">Heat shock response</span> Type of cellular stress response

The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal cell, proteostasis must be maintained because proteins are the main functional units of the cell. Many proteins take on a defined configuration in a process known as protein folding in order to perform their biological functions. If these structures are altered, critical processes could be affected, leading to cell damage or death. The heat shock response can be employed under stress to induce the expression of heat shock proteins (HSP), many of which are molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.

<span class="mw-page-title-main">MRC Laboratory of Molecular Biology</span> Research institute in Cambridge, England

The Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) is a research institute in Cambridge, England, involved in the revolution in molecular biology which occurred in the 1950–60s. Since then it has remained a major medical research laboratory at the forefront of scientific discovery, dedicated to improving the understanding of key biological processes at atomic, molecular and cellular levels using multidisciplinary methods, with a focus on using this knowledge to address key issues in human health.

In eukaryotic cells, an aggresome refers to an aggregation of misfolded proteins in the cell, formed when the protein degradation system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize misfolded proteins into a single location.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Proteinopathy</span> Medical condition

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.

<span class="mw-page-title-main">UBQLN1</span> Protein-coding gene in the species Homo sapiens

Ubiquilin-1 is a protein that in humans is encoded by the UBQLN1 gene.

<span class="mw-page-title-main">Protein aggregation</span> Accumulation of clumps of misfolded or disordered proteins

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

Richard I. Morimoto is a Japanese American molecular biologist. He is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University.

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies.

<span class="mw-page-title-main">JUNQ and IPOD</span> Types of cytosolic protein inclusion bodies

JUNQ and IPOD are types of cytosolic protein inclusion bodies in eukaryotes.

<span class="mw-page-title-main">Ramanujan Hegde</span> British-Indian biochemist (born 1970)

Ramanujan Shankar Hegde is a group leader at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB).

Chaperome refers to the ensemble of all cellular molecular chaperone and co-chaperone proteins that assist protein folding of misfolded proteins or folding intermediates in order to ensure native protein folding and function, to antagonize aggregation-related proteotoxicity and ensuing protein loss-of-function or protein misfolding-diseases such as the neurodegenerative diseases Alzheimer's, Huntington's or Parkinson's disease, as well as to safeguard cellular proteostasis and proteome balance.

<span class="mw-page-title-main">Felix Armin Randow</span>

Felix Armin Randow is a German molecular immunologist and tenured group leader at the MRC Laboratory of Molecular Biology in Cambridge. Guided by the importance of cell-autonomous immunity as the sole defender of unicellular organisms, Randow has made contributions to the understanding of host-pathogen interactions. He is an EMBO member, a Wellcome Trust investigator and a Fellow of the Academy of Medical Sciences.

<span class="mw-page-title-main">Lori Passmore</span> Canadian/British scientist

Lori Anne Passmore is a Canadian/British cryo electron microscopist and structural biologist who works at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) at the University of Cambridge. She is known for her work on multiprotein complexes involved in gene expression and development of new supports for cryo-EM.

<span class="mw-page-title-main">Andrew P. Carter</span> British structural biologist

Andrew P. Carter is a British structural biologist who works at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) in Cambridge, UK. He is known for his work on the microtubule motor dynein.

<span class="mw-page-title-main">Melina Schuh</span> German molecular biologist

Melina Schuh is a German biochemist and Director at the Max Planck Institute for Multidisciplinary Sciences. She is known for her work on meiosis in mammalian oocytes, for her studies on the mechanisms leading to the age-related decline in female fertility, and for the development of the Trim-Away protein depletion method.

<span class="mw-page-title-main">Michele Vendruscolo</span> Italian British physicist

Michele Vendruscolo is an Italian British physicist working in the UK, noted for his theoretical and experimental work on protein folding, misfolding and aggregation.

<span class="mw-page-title-main">Fabrizio Chiti</span> Italian biochemist

Fabrizio Chiti is an Italian biochemist noted for his work on Protein aggregation and amyloid.

<span class="mw-page-title-main">M. Madan Babu</span> Indian-American computational biologist

M. Madan Babu is an Indian-American computational biologist and bioinformatician. He is the endowed chair in biological data science and director of the center of excellence for data-driven discovery at St. Jude Children’s Research Hospital. Previously, he served as a programme leader at the MRC Laboratory of Molecular Biology (LMB).

References

  1. 1 2 3 "Dr Anne Bertolotti | The Academy of Medical Sciences". acmedsci.ac.uk. Retrieved 2020-03-07.
  2. ↑ Biology, ©2020 MRC Laboratory of Molecular; Avenue, Francis Crick; Campus, Cambridge Biomedical; CB2 0QH, Cambridge; Uk. 01223 267000. "Anne Bertolotti". MRC Laboratory of Molecular Biology. Retrieved 2020-09-30.{{cite web}}: CS1 maint: numeric names: authors list (link)
  3. ↑ pmabbs (2022-10-14). "Anne Bertolotti appointed as Joint Head of the LMB's Neurobiology Division". MRC Laboratory of Molecular Biology. Retrieved 2023-03-28.
  4. 1 2 3 "Biochemical Society 2018 Award Winners".
  5. 1 2 3 4 "Hooke Medal Winner 2014 – Anne Bertolotti | British Society for Cell Biology" . Retrieved 2020-03-07.
  6. ↑ Bertolotti, Anne; Zhang, Yuhong; Hendershot, Linda M.; Harding, Heather P.; Ron, David (June 2000). "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology. 2 (6): 326–332. doi:10.1038/35014014. ISSN   1476-4679. PMID   10854322. S2CID   22684712.
  7. ↑ Harding, Heather P.; Zhang, Yuhong; Bertolotti, Anne; Zeng, Huiqing; Ron, David (2000-05-01). "Perk Is Essential for Translational Regulation and Cell Survival during the Unfolded Protein Response". Molecular Cell. 5 (5): 897–904. doi: 10.1016/S1097-2765(00)80330-5 . ISSN   1097-2765. PMID   10882126.
  8. ↑ Bertolotti, Anne; Ron, David (2001-09-01). "Alterations in an IRE1-RNA complex in the mammalian unfolded protein response". Journal of Cell Science. 114 (17): 3207–3212. doi:10.1242/jcs.114.17.3207. ISSN   0021-9533. PMID   11590247.
  9. ↑ "Anne Bertolotti • iBiology". iBiology. Retrieved 2020-09-30.
  10. ↑ "Bertolotti A[Author] - Search Results - PubMed". PubMed. Retrieved 2020-09-30.
  11. ↑ Rousseau, Erwann; Dehay, Benjamin; Ben-Haïem, Léa; Trottier, Yvon; Morange, Michel; Bertolotti, Anne (2004-06-29). "Targeting expression of expanded polyglutamine proteins to the endoplasmic reticulum or mitochondria prevents their aggregation". Proceedings of the National Academy of Sciences. 101 (26): 9648–9653. Bibcode:2004PNAS..101.9648R. doi: 10.1073/pnas.0403015101 . ISSN   0027-8424. PMC   470729 . PMID   15210964.
  12. ↑ Dehay, Benjamin; Bertolotti, Anne (2006-11-24). "Critical role of the proline-rich region in Huntingtin for aggregation and cytotoxicity in yeast". The Journal of Biological Chemistry. 281 (47): 35608–35615. doi: 10.1074/jbc.M605558200 . ISSN   0021-9258. PMID   16973603. S2CID   19848703.
  13. ↑ Rousseau, Erwann; Kojima, Rieko; Hoffner, Guylaine; Djian, Philippe; Bertolotti, Anne (2009-01-16). "Misfolding of Proteins with a Polyglutamine Expansion Is Facilitated by Proteasomal Chaperones". The Journal of Biological Chemistry. 284 (3): 1917–1929. doi: 10.1074/jbc.M806256200 . ISSN   0021-9258. PMC   2615503 . PMID   18986984.
  14. ↑ Münch, Christian; Bertolotti, Anne (2010-06-11). "Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants". Journal of Molecular Biology. 399 (3): 512–525. doi:10.1016/j.jmb.2010.04.019. ISSN   1089-8638. PMC   2927901 . PMID   20399791.
  15. ↑ Münch, Christian; O’Brien, John; Bertolotti, Anne (2011-03-01). "Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells". Proceedings of the National Academy of Sciences. 108 (9): 3548–3553. Bibcode:2011PNAS..108.3548M. doi: 10.1073/pnas.1017275108 . ISSN   0027-8424. PMC   3048161 . PMID   21321227.
  16. ↑ Zhong, Zhen; Grasso, Laura; Sibilla, Caroline; Stevens, Tim J.; Barry, Nicholas; Bertolotti, Anne (15 March 2018). "Prion-like protein aggregates exploit the RHO GTPase to cofilin-1 signaling pathway to enter cells". The EMBO Journal. 37 (6). doi:10.15252/embj.201797822. ISSN   1460-2075. PMC   5852416 . PMID   29496740.
  17. ↑ Suraweera, Amila; Münch, Christian; Hanssum, Ariane; Bertolotti, Anne (2012-10-26). "Failure of Amino Acid Homeostasis Causes Cell Death following Proteasome Inhibition". Molecular Cell. 48 (2): 242–253. doi:10.1016/j.molcel.2012.08.003. ISSN   1097-2765. PMC   3482661 . PMID   22959274.
  18. ↑ Hanssum, Ariane; Zhong, Zhen; Rousseau, Adrien; Krzyzosiak, Agnieszka; Sigurdardottir, Anna; Bertolotti, Anne (2014-08-21). "An Inducible Chaperone Adapts Proteasome Assembly to Stress". Molecular Cell. 55 (4): 566–577. doi:10.1016/j.molcel.2014.06.017. ISSN   1097-2765. PMC   4148588 . PMID   25042801.
  19. ↑ Rousseau, Adrien; Bertolotti, Anne (August 2016). "An evolutionarily conserved pathway controls proteasome homeostasis". Nature. 536 (7615): 184–189. Bibcode:2016Natur.536..184R. doi:10.1038/nature18943. ISSN   1476-4687. PMC   4990136 . PMID   27462806.
  20. 1 2 Tsaytler, Pavel; Harding, Heather P.; Ron, David; Bertolotti, Anne (2011-04-01). "Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis". Science. 332 (6025): 91–94. Bibcode:2011Sci...332...91T. doi: 10.1126/science.1201396 . ISSN   1095-9203. PMID   21385720. S2CID   3169931.
  21. 1 2 Das, Indrajit; Krzyzosiak, Agnieszka; Schneider, Kim; Wrabetz, Lawrence; D'Antonio, Maurizio; Barry, Nicholas; Sigurdardottir, Anna; Bertolotti, Anne (2015-04-10). "Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit". Science. 348 (6231): 239–242. Bibcode:2015Sci...348..239D. doi:10.1126/science.aaa4484. ISSN   1095-9203. PMC   4490275 . PMID   25859045.
  22. ↑ Carrara, Marta; Sigurdardottir, Anna; Bertolotti, Anne (September 2017). "Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors". Nature Structural & Molecular Biology. 24 (9): 708–716. doi:10.1038/nsmb.3443. ISSN   1545-9985. PMC   5591645 . PMID   28759048.
  23. 1 2 Krzyzosiak, Agnieszka; Sigurdardottir, Anna; Luh, Laura; Carrara, Marta; Das, Indrajit; Schneider, Kim; Bertolotti, Anne (23 August 2018). "Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B". Cell. 174 (5): 1216–1228.e19. doi:10.1016/j.cell.2018.06.030. ISSN   1097-4172. PMC   6108835 . PMID   30057111.
  24. 1 2 "Protein Phosphatases • iBiology". iBiology. Retrieved 2020-09-30.
  25. ↑ "A Combined SAD and MAD Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088 - Tabular View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-09-30.
  26. ↑ "EMBO report 2004" (PDF).
  27. ↑ "Dr. Anne Bertolotti – Building Bridges in Medical Sciences" . Retrieved 2020-09-30.
  28. ↑ "EMBO announces new members for 2013". EMBO. Archived from the original on 2019-05-11. Retrieved 2020-03-07.
  29. ↑ "7 novembre 2019: Prof. Anne Bertolotti - Frontiers in biomedicine - UNIGE". www.unige.ch. 2019-08-08. Retrieved 2020-09-30.
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