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Structural insight into binding of novel PET tracer MODAG-005 to lipidic α -Synuclein fibrils

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Titel: Structural insight into binding of novel PET tracer MODAG-005 to lipidic α -Synuclein fibrils
Autoren: Myeongkyu Kim, Dirk Matthes, Benedikt Frieg, Andrei Leonov, Sergey Ryazanov, Daniel Bleher, Ann-Kathrin Grotegerd, Christian Dienemann, Armin Giese, Gunnar F. Schröder, Stefan Becker, Kristina Herfert, Bert L. de Groot, Loren B. Andreas, Christian Griesinger
Verlagsinformationen: Cold Spring Harbor Laboratory, 2025.
Publikationsjahr: 2025
Beschreibung: Accumulation of α-synuclein (αSyn) aggregates in the human brain is the major hallmark of synucleinopathies such as Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy bodies. Positron Emission Tomography (PET) plays a vital role in diagnosing these diseases and monitoring their progression by enabling the non-invasive and sensitive detection of αSyn aggregates in the brain. However, developing PET tracers with specific target binding, as well as identifying the binding site and complex structure present significant challenges. Here, we investigated the interaction between lipidic αSyn aggregates and MODAG-005, a new αSyn PET tracer candidate, using nuclear magnetic resonance spectroscopy, cryogenic electron microscopy and molecular dynamics (MD) simulations. Two binding sites of MODAG-005 were found, one on the surface and one in a tubular cavity of the fibril, of which the occupancies were found to depend on the preparation protocols. The cavity binding site is thermodynamically more stable than the external binding site and is the only site occupied when MODAG-005 is applied with liposome as carriers to the aggregates. This is corroborated by MD simulations in which stable interactions between MODAG-005 and glycine containing backbone motifs of the tubular cavity of the aggregates are observed.
Publikationsart: Article
DOI: 10.1101/2025.04.21.649837
Rights: CC BY NC ND
Dokumentencode: edsair.doi...........56fdd6449561adced3f2085fcd2969fc
Datenbank: OpenAIRE
Beschreibung
Abstract:Accumulation of α-synuclein (αSyn) aggregates in the human brain is the major hallmark of synucleinopathies such as Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy bodies. Positron Emission Tomography (PET) plays a vital role in diagnosing these diseases and monitoring their progression by enabling the non-invasive and sensitive detection of αSyn aggregates in the brain. However, developing PET tracers with specific target binding, as well as identifying the binding site and complex structure present significant challenges. Here, we investigated the interaction between lipidic αSyn aggregates and MODAG-005, a new αSyn PET tracer candidate, using nuclear magnetic resonance spectroscopy, cryogenic electron microscopy and molecular dynamics (MD) simulations. Two binding sites of MODAG-005 were found, one on the surface and one in a tubular cavity of the fibril, of which the occupancies were found to depend on the preparation protocols. The cavity binding site is thermodynamically more stable than the external binding site and is the only site occupied when MODAG-005 is applied with liposome as carriers to the aggregates. This is corroborated by MD simulations in which stable interactions between MODAG-005 and glycine containing backbone motifs of the tubular cavity of the aggregates are observed.
DOI:10.1101/2025.04.21.649837