Project

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Molecular and Cellular Modulation in Parkinson's Disease

Applicant Stahlberg Henning
Number 177195
Funding scheme Sinergia
Research institution EPFL Laboratory of Biological Electron Microscopy Institute of Physics (IPHYS)
Institution of higher education EPF Lausanne - EPFL
Main discipline Interdisciplinary
Start/End 01.01.2018 - 30.06.2022
Approved amount 3'111'590.00
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All Disciplines (5)

Discipline
Interdisciplinary
Biophysics
Biochemistry
Molecular Biology
Neurophysiology and Brain Research

Keywords (7)

Neurodegeneration; limited proteolysis mass spectrometry; systems biology; GWAS; in-cell NMR; Parkinson's disease; electron microscopy

Lay Summary (German)

Lead
Die Parkinson’sche Krankheit (Parkinson) ist eine schwere neurodegenerative Erkrankung, von welcher etwa 2% der Bevölkerung betroffen werden. Wie auch bei der Alzheimer’sche oder der Huntington’schen Krankheit wird bei Parkinson angenommen, dass es eine sogenannte Aggregations-Krankheit ist, bei welcher im Fall von Parkinson ein Protein namens Alpha-Synuclein (aSyn) in unseren Neuronen zu prionen-artigen Fibrillen aggregiert. Das Protein aSyn wird im Gehirn von Parkinson Patienten auch in grossen Klumpen, sogenannten Lewy Bodies, angereichert gefunden. Die genauen Mechanismen, ob und wie das Protein aSyn, oder die Lewy Bodies zu der Krankheit beitragen, sind nicht bekannt.
Lay summary

In diesem SINERGIA Projekt werden wir die Parkinson’sche Krankheit strukturell, genetisch, biochemisch, und dynamisch untersuchen. Hierzu werden wir menschliche Gehirnproben von verstorbenen Parkinson Patienten auf Anomalitäten untersuchen, und gewonnene Erkenntnisse in Zellkulturen im Labor nachstellen. Neben aSyn werden wir nach anderen unbekannten Proteinen suchen, welche auch in der Krankheit involviert sind. Wir werden in Modell-Zellkulturen die identifizierten Proteine herstellen, und deren Struktur und deren Funktion und Einfluss auf die weitere Zellbiologie untersuchen.

 

Mit dieser Forschung erhoffen wir uns die Identifikation von neuen Medikamenten Zielmolekülen, hoffen auf ein besseres Verständniss der molekularen Vorgänge in der Parkinson’schen Krankheit, und hoffen, PET Tracer Moleküle oder Therapie-Strategien entwickeln zu können.

Direct link to Lay Summary Last update: 16.02.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins
Melnik Andre, Cappelletti Valentina, Vaggi Federico, Piazza Ilaria, Tognetti Marco, Schwarz Carmen, Cereghetti Gea, Ahmed Mennat Allah, Soste Martin, Matlack Kent, de Souza Natalie, Csikasz-Nagy Attila, Picotti Paola (2020), Comparative analysis of the intracellular responses to disease-related aggregation-prone proteins, in Journal of Proteomics, 225, 103862-103862.
α-Synuclein aggregation nucleates through liquid–liquid phase separation
Ray Soumik, Singh Nitu, Kumar Rakesh, Patel Komal, Pandey Satyaprakash, Datta Debalina, Mahato Jaladhar, Panigrahi Rajlaxmi, Navalkar Ambuja, Mehra Surabhi, Gadhe Laxmikant, Chatterjee Debdeep, Sawner Ajay Singh, Maiti Siddhartha, Bhatia Sandhya, Gerez Juan Atilio, Chowdhury Arindam, Kumar Ashutosh, Padinhateeri Ranjith, Riek Roland, Krishnamoorthy G., Maji Samir K. (2020), α-Synuclein aggregation nucleates through liquid–liquid phase separation, in Nature Chemistry, online.
Detecting Protein–Small Molecule Interactions Using Limited Proteolysis–Mass Spectrometry (LiP-MS)
Pepelnjak Monika, de Souza Natalie, Picotti Paola (2020), Detecting Protein–Small Molecule Interactions Using Limited Proteolysis–Mass Spectrometry (LiP-MS), in Trends in Biochemical Sciences, online.
Mass spectrometry analysis of the structural proteome
de Souza Natalie, Picotti Paola (2020), Mass spectrometry analysis of the structural proteome, in Current Opinion in Structural Biology, 60, 57-65.
Regulation of α-synuclein by chaperones in mammalian cells
Burmann Björn M., Gerez Juan A., Matečko-Burmann Irena, Campioni Silvia, Kumari Pratibha, Ghosh Dhiman, Mazur Adam, Aspholm Emelie E., Šulskis Darius, Wawrzyniuk Magdalena, Bock Thomas, Schmidt Alexander, Rüdiger Stefan G. D., Riek Roland, Hiller Sebastian (2020), Regulation of α-synuclein by chaperones in mammalian cells, in Nature, 577(7788), 127-132.
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1)
Jenkins Kirsten, Mateeva Teodora, Szabó István, Melnik Andre, Picotti Paola, Csikász-Nagy Attila, Rosta Edina (2020), Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1), in Computational and Structural Biotechnology Journal, 18, 1032-1042.
Half a century of amyloids: past, present and future
Ke Pu Chun, Zhou Ruhong, Serpell Louise C., Riek Roland, Knowles Tuomas P. J., Lashuel Hilal A., Gazit Ehud, Hamley Ian W., Davis Thomas P., Fändrich Marcus, Otzen Daniel Erik, Chapman Matthew R., Dobson Christopher M., Eisenberg David S., Mezzenga Raffaele (2020), Half a century of amyloids: past, present and future, in Chemical Society Reviews, online.
Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
Guerrero-Ferreira Ricardo, Taylor Nicholas MI, Arteni Ana-Andreea, Kumari Pratibha, Mona Daniel, Ringler Philippe, Britschgi Markus, Lauer Matthias E, Makky Ali, Verasdonck Joeri, Riek Roland, Melki Ronald, Meier Beat H, Böckmann Anja, Bousset Luc, Stahlberg Henning (2019), Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy, in eLife, 8, e48907.
15N transverse relaxation measurements for the characterization of µs–ms dynamics are deteriorated by the deuterium isotope effect on 15N resulting from solvent exchange
Kumari Pratibha, Frey Lukas, Sobol Alexander, Lakomek Nils-Alexander, Riek Roland (2018), 15N transverse relaxation measurements for the characterization of µs–ms dynamics are deteriorated by the deuterium isotope effect on 15N resulting from solvent exchange, in Journal of Biomolecular NMR, 72(3-4), 125-137.
Cryo-EM structure of alpha-synuclein fibrils
Guerrero-Ferreira Ricardo, Taylor Nicholas MI, Mona Daniel, Ringler Philippe, Lauer Matthias E, Riek Roland, Britschgi Markus, Stahlberg Henning (2018), Cryo-EM structure of alpha-synuclein fibrils, in eLife, 7, e36402.
Cryo-EM structure of alpha-synuclein fibrils
Guerrero-Ferreira Ricardo, Taylor Nicholas MI, Mona Daniel, Ringler Philippe, Lauer Matthias E, Riek Roland, Britschgi Markus, Stahlberg Henning (2018), Cryo-EM structure of alpha-synuclein fibrils, in eLife, 7, e36402.
Rational Structure‐Based Design of Fluorescent Probes for Amyloid Folds
Orts Julien, Wälti Marielle Aulikki, Ghosh Dhiman, Campioni Silvia, Saupe Sven J., Riek Roland (2018), Rational Structure‐Based Design of Fluorescent Probes for Amyloid Folds, in chembiochem, 20, 0-0.

Associated projects

Number Title Start Funding scheme
154461 The Time- and Spatially Resolved Aggregation of a-Synuclein and its Relationship to Cell-Cell Transmissibility 01.10.2014 Sinergia
188548 Structural Studies of Human Brain in Neurodegeneration 01.08.2020 Project funding (Div. I-III)
200628 Coherent Electron Diffractive Imaging for Vitrified Single Protein Particles 01.09.2021 Project funding (Div. I-III)

Abstract

Parkinson's Disease (PD) is a prominent and severe neurodegenerative disease of age that affects about 2% of our population. It is considered to be one of the protein aggregation diseases, which also include Alzheimer’s disease or Huntington's disease. In PD, dopaminergic neurons in the substantia nigra (SN) region of the brain are lost, yielding the typical disease symptoms of tremor or slowness of movement and rigidity. The pathological hallmarks of PD are large aggregates within the affected neurons, which are called Lewy bodies or Lewy neurites, and which are composed of lipids and the protein alpha-synuclein (a-Syn). Familial PD is often related to mutants at the a-Syn gene locus, while recent genome-wide association studies identified several other so called “PD risk genes”. Despite several decades of intensive research on PD, the molecular mechanism behind neurodegeneration and the involved protein players are not known. Early diagnosis of the disease with positron-emission tomography (PET) is so far not possible, because a suita-ble protein target for a PET tracer is not identified. Medical treatment of PD so far can only weaken the symptoms of the disease, but cannot prevent or slow-down or stop its progression. No cell line or animal model exists that is seen as a full representative for the disease.In this 4-year Sinergia project, we will study Parkinson's disease from a structural perspective in situ, using hu-man brain tissue and fluids from PD patients. We will translate this information to the cellular level and to animal mod-els for detailed structural, dynamical and cell biological analysis, and compare these findings with those obtained from human samples. In parallel, we will analyze the structural and dynamical consequences of “PD risk gene” proteins with-in model cell. This project will use systems-biology screens, GWAS analysis, and employ three complementary structural methods: Cryo-electron microscopy and tomography will be used to elucidate both protein conformations and tissue structure at high resolution; Conformation-sensitive mass spectrometry based on limited proteolysis will be used to fingerprint the structures and alterations of structures of various proteins, comparing these between healthy and PD tissue and model cells; And finally, in-cell NMR will be used to determine the 3D structure and dynamics including the identification of transient interactors of a-Syn and other proteins of interest at near-atomic resolution within the cells. These three structural methods are able to study structures and structural alterations within the physiological mi-lieu. This will be complemented with a systems biology approach at the cell level to elucidate the biological conse-quences of the structural alterations. The proteins encoded by the “PD risk genes” will be characterized for their struc-tural and biochemical impact on the biology of the cell. And finally, the structure and function of specific, identified proteins of interest with relevancy in PD neurodegeneration will be determined. The unique combination of methods employed here, and their application to human PD brain tissue, and cell and animal models for PD will allow screening for novel proteins that may be so far unrecognized players in the develop-ment of PD. This research will provide a better mechanistic insight into the molecular processes underlying the progres-sion of neurodegeneration in Parkinson's disease, and may identify novel PET tracer or even drug targets to understand and treat this debilitating disease.
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