研究棟201室

NMR spectroscopy is a powerful tool to study dynamics and kinetics of conformational ensembles (1). While pico-second to one digit nano-seconds are well covered by relaxation measurements and several 10 micro-seconds to millisecond by relaxation dispersion, relying on the variation of isotropic chemical shifts, the region between one digit nano-seconds and several 10 micro-seconds is difficult to access. High power relaxation dispersion specifically of ¹H and ¹⁹F can assess the amount and kinetics of motion in this region. This will be discussed in the context of protein motion with approaches to get information about the time region between ns and µs.

The importance of optimal control pulses for highest field NMR (1.2 GHz) and large volume probes of proteins will be presented (2).

A major effort in the department is on the structural characterization of aggregates that play a role in neurodegeneration. By including lipids in the aggregation process in vitro, we aim at reconstituting physiologically relevant aggregates (3). Indeed, in the aggregation process, intermediate 1, intermediate 2 and the fibrillar endpoint are structurally characterized. Intermediate 1 (Int1) is toxic to cells and the structure of Int1 is a lipidic tetramer (4). From Int1’s structure, ion flux through membranes can be rationalized. When anle138b, a clinical drug candidate for the treatment of various neurodegenerative diseases including Parkinson’s, Alzheimer’s and Huntington’s disease, Multiple System Atrophy, and type II diabetes mellitus (5), is added during the aggregation process, the anle138b modified Int1 loses toxicity. In line with this, inhibition of ion conductivity can be rationalized from the modified structure and different stoichiometry. Int1 and anle138b modified Int1 show different effects on proteostasis which will be discussed. Emerging commonalities of the detoxification mechanism of anle138b on Aβ oligomers will be presented.

We have characterized a novel PET tracer candidate (6) for diseases linked to a-synuclein aggregation, MODAG-005, in vitro as as well as in humans. Its binding mode to lipidic fibrils (6) will be discussed and compared to the binding mode of anle138b (7).

References:

1) Smith CA, Ban D, Pratihar S, Giller K, Schwiegk C, de Groot BL, Becker S, Griesinger C, Lee D, Population Shuffling of Protein Conformations. Angew. Chem. Int. Ed. 54, 207-10 (2015); Smith CA, Ban D, Pratihar S, Giller K, Paulat M; Becker S, Griesinger C, Lee D, de Groot BL. “Allosteric switch regulates protein-protein binding through collective motion” Proc. Natl. Acad. Sci. USA. 113, 3296-74 (2016); Chakrabarti KS, Olsson S, Pratihar S, Giller K, Overkamp K, Lee KO, Gapsys V, Ryu KS, de Groot BL, Noé F, Becker S, Lee D, Weikl TR, Griesinger C. A litmus test for classification of recognition mechanisms of transiently binding proteins. Nature Commun. 13 (1) 3792 (2022); Szöllősi D, Pratihar S, Mukhopadhyay D, Kumar Rout A, Han M, Reddy GJ, Ebersberger N, Becker S, Nagy G, Rauscher S, Lee D, Klement R, Griesinger C, Grubmüller H. Nature Commun. 17, 4812 (2026)

2) Joseph D, Griesinger C Optimal Control pulses for the 1.2 GHz (28.2 T) NMR spectrometers Sci. Adv. 9, eadj1133 (2023); Joseph D, Kümmerle R, Freytag N, Griesinger C, Advancing GHz-class NMR: High sensitivity through larger volume cryoprobe and optimal control sequences JMR 389, 108081 (2026)

3) Antonschmidt L, Dervişoğlu R, Sant V, Movellan KT, Mey I, Riedel D, Steinem C, Becker S, Andreas LB, Griesinger C. Insights into the molecular mechanism of amyloid filament formation: segmental folding of α-synuclein on lipid membranes/Molecular mechanism of αS filament folding on membranes, Sci. Adv. 7(20) eabg2174

4) Sant V, Matthes D, Mazal H, Antonschmidt L, Wieser F, Movellan KT, Xue K, Nimerovsky E, Nathan M, Becker S, Sandoghdar V, deGroot B, Griesinger C, Andreas LB Structure of a lipidic α-Synuclein misfolded aggregation intermediate Nat. Commun. 16:760 (2025)

5) Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bähr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Bötzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A, “Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease”, Acta Neuropathol. 125, 795-813 (2013); Wegrzynowicz M, Bar-On D, Calò L, Anichtchik O, Iovino M, Xia J, Ryazanov S, Leonov A, Giese A, Dalley JW, Griesinger C, Ashery U, Spillantini MG. “Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson disease model” Acta Neuropathol. 138, 575-595 (2019); Levin J, Sing N, Melbourne S, Morgan A, Spillantini MG, Wegrzynowicz M, Dalley JW, Ryazanov S, Leonov A, Griesinger C, Schmidt F, Weckbecker D, Prager K, Matthias T, Giese A. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: a randomised, double-blind, placebo-controlled phase 1 trial EBioMedicine 80, 104021 (2022); NCT04685265; Albariqi MMH, Baauw SMG, Fens SJPJ, Versteeg S, Ryazanov S, Leonov A, Willemen HLDM, Stathonikos N, Seychell RM, El Saghir A, Khemtemourian L, Vassallo N, Giese A, Eijkelkamp N, Griesinger C, Höppener JWM. The amyloid oligomer modulator anle138b has disease modifying effects in a human IAPP transgenic mouse model of type 2 diabetes mellitus (hIAPP Ob/Ob mice) https://doi.org/10.1101/2024.08.27.609850; da Silva Padilha M, Koyuncu S, Chabanis E, Ryazanov S, Leonov A, Vilchez D, Klein R, Giese A, Griesinger C and Dudanova I. Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease EMBO Mol. Med. 18, 2838–2866 (2026)

6) Buss S, Saw RS, Kuebler L, Schmidt F, Ryazanov S, Leonov A, Bleher D, Bonanno F, Grotegerd AK, Ruf VC, Henry KE, Sandiego CM, Pichler BJ, Maurer A, Griesinger C, Giese A, Herfert K. [¹¹C]MODAG‑005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain. Science Translational Medicine 18, eaec0813 (2026); Kim M, Matthes D, Frieg B, Leonov A, Ryazanov S, Bleher D, Grotegerd AK, Dienemann C, Giese A, Schröder GF, Becker S, Herfert K, de Groot NL, Andreas LB, Griesinger C. Structural insight into binding of novel PET tracer MODAG-005 to lipidic α-Synuclein fibrils doi: https://doi.org/10.1101/2025.04.21.649837

7) Frieg B, Antonschmidt L, Dienemann C, Geraets A, Matthes D, de Groot BL, Becker S, Andreas LB, Griesinger C, Schröder GF. Lipid-induced polymorphism of α-synuclein fibrils: Nat. Commun. 13, 6810 (2022); Antonschmidt L, Dervişoğlu R, Matthes D, Dienemann C, Leonov A, Sant A, Ryazanov S, Becker S, Giese A, Schröder GF, de Groot BL, Griesinger C_, Andreas LB. The small molecule drug candidate anle138b is incorporated into α-synuclein fibrils Nat. Commun. (2022) 13:5385; Frieg B, Han M, Giller K, Dienemann C, Riedel D, Becker S, Andreas LB, Griesinger C, and Schröder GF. Cryo-EM structures of lipidic fibrils of amyloid-β(1-40) Nature Commun. 15, Article number: 1297 (2024); Han M Frieg B, Matthes D, Leonov A, Ryazanov S, Giller K, Nimerovsky E, Stampolaki M, Xue K, Overkamp K, Dienemann C, Riedel D, Giese A, Becker S, de Groot BL, Schröder GF, Andreas LB and Griesinger C. Drug Candidate Anle138b demonstrates predominant binding to the internal cavity of Lipidic Amyloid Beta 40 fibrils Nat. Comm. 16, 8850 (2025)

飯野 亮太 (生命・錯体分子科学研究領域)
岡崎圭一、岡本泰典 (2026年度コロキウム委員)