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Protein aggregation diseases (b/d PAD)

Protein aggregation diseases (PAD), exemplified by Parkinson’s or Alzheimer’s disease and systemic amyloidoses, are characterized by an abnormal deposition of protein aggregates of regular three-dimensional structure (amyloid). The B/D PAD working group aims at developing proteomics assays for proteins that are relevant to the study, diagnosis and therapy of protein aggregation diseases. These assays will be tested and refined on a set of relevant patient samples (for clinical applications) and on samples from model organisms and cell culture (for basic research). The assays will be made publicly available through web-based databases such as the SRMAtlas or PRIDE. Initially the assays will consist of standardized (scheduled) SRM coordinates from triple-quadrupole instruments and spectral libraries from shotgun proteomics measurements. We will also consider generating SWATH/data-independent fragment ion maps for relevant samples. Besides developing assays for measuring protein abundances, a peculiarity of our initiative is that it will attempt also the development of proteomics assays for “aberrant protein conformations”, those typically generated in PADs. The idea relies on a recently published method involving SRM and proteolytic markers (LiP-SRM, Feng et al., Nat. Biotechnology, 2014). The conformational assays for “functional” and “pathological” conformational states of each amyloidogenic protein will also consist of SRM coordinates. 

    Current lines of work:

    • Definition of priority protein lists relevant in protein misfolding diseases
    • To develop targeted standardized methods for the quantification of clinically relevant proteins
    • Evaluating the potential use of such proteins for the diagnosis and subtyping of local and systemic amyloidoses and the possibility to transfer the associated targeted proteomics assays to the clinical environment
    • Identification of novel proteins relevant to protein aggregation diseases by means of proteomics approaches coupled to systems-biology tools
    • Structural analysis of proteins involved in protein misfolding diseases by structural proteomics tools and evaluation of the concept of “structural biomarkers of disease”

      Current group members:

      1. Paola Picotti (ETH Zurich, CH, chair) (Proteomics, MS)
      2. Bouke Hazenberg (Univ. of Groningen, NL) (Clinician)
      3. Gyorgy Marko-Varga/Melinda Rezeli (Univ. of Lund, Sweden) (Proteomics, MS)
      4. Roman Zubarev (Karolinska Inst., Sweden) (Proteomics, MS)
      5. Giampaolo Merlini (University of Pavia, Italy) (Clinician)
      6. Catherine Costello (Boston Univ., MA, USA) (Proteomics, MS)
      7. Roger Nitsch (Univ of Zurich, CH) (Clinician)
      8. Erik Portelius (Univ. of Gothenburg, Sweden) (Proteomics, MS)
      9. Keding Cheng (Public Health Agency of Canada) (Proteomics, MS)

      Links:

      Papers:

      1. Boersema, PJ, Bijzet, J, Zimmerli, C, Huang, T, Vitek, O, Hazenberg, BPB, Picotti, P. A novel mass spectrometry based assay for the diagnosis and typing of systemic amyloidosis (in preparation)
      2. Rezeli M, Zetterberg H, Blennow K, Brinkmalm A, Laurell T, Hansson O, Marko-Varga G. Quantification of total apolipoprotein E and its specific isoforms in cerebrospinal fluid and blood in Alzheimer’s disease and other neurodegenerative diseases. (2015) EuPA Open Proteomics, 8, 137-143.
      3. Welinder C, Jonsson GB, Ingvar C, Lundgren L, Baldetorp B, Olsson H, Breslin T, Rezeli M, Jansson B, Fehniger TE, Laurell T, Wieslander E, Pawlowski K, Marko-Varga G. Analysis of Alpha-Synuclein in Malignant Melanoma - Development of a SRM Quantification Assay. (2014) PLOS ONE, 9(10), e110804
      4. Gerez J, Adame A, Enchev R, Courtheoux T, Boersema P, Peter M, Masliah E, Picotti P. The SKP1-Cul1-FBXL5 ubiquitin ligase targets extracellular α-synuclein and inhibits Lewy Body pathology (under review)

      Leadership:

      Paola Picotti, Chair

      Melinda Rezeli, Co-Chair

      For more information or participation opportunities please contact office(at)hupo.org.



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