Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson’s disease<i>in vivo</i>

Straumann, Nadja; Combes, Benjamin F.; Ben, Xose Luis Dean; Sternke-Hoffmann, Rebecca; Gerez, Juan A.; Dias, Ines; Chen, Zhenyue; Watts, Benjamin; Rostami, Iman; Shi, Kuangyu; Rominger, Axel; Baumann, Christian R; Luo, Jinghui; Noain, Daniela; Nitsch, Roger M.; Okamura, Nobuyuki; Razansky, Daniel; Ni, Ruiqing

doi:10.1101/2023.06.28.546962

Cited by 3 publications

References 70 publications

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Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

Sobek,

Li,

Combes

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. Methods SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson’s disease patients and mouse models was performed with fluorescence ligands and specific antibodies. Results We optimized the protocol for the immobilization of Aβ42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson’s disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice. Conclusion SPR measurements of small molecules binding to Aβ42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

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Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

Sobek,

Li,

Combes

et al. 2024

Eur J Nucl Med Mol Imaging

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Imaging increased metabolism in the spinal cord in mice after middle cerebral artery occlusion

Straumann

Fazio

et al. 2023

Photoacoustics

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Spinal cord perfusion impairments in the M83 mouse model of Parkinson’s disease

Combes,

Kalva,

Benveniste

et al. 2024

Preprint

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Metabolism and bioenergetics in the central nervous system play important roles in the pathophysiology of Parkinson's disease (PD). Here, we employed a multimodal imaging approach to assess oxygenation changes in the spinal cord of a transgenic M83 murine model of PD in comparison to non-transgenic littermates at 9-12 months-of-age. A lower oxygen saturation (SO2)SVOT was detected in vivo with spiral volumetric optoacoustic tomography (SVOT) in the spinal cord of M83 mice compared to non-transgenic littermate mice. Ex-vivo high-field T1-weighted magnetic resonance imaging (MRI) and immunostaining for alpha-synuclein (phospho-S129) and vascular organisation (CD31 and GLUT1) were used to investigate the nature of the abnormalities detected via in vivo imaging. Ex-vivo analysis showed that the vascular network in the spinal cord was not impaired in the spinal cord of M83 mice. Ex-vivo MRI assisted with deep learning-based automatic segmentation showed no volumetric atrophy in the spinal cord of M83 mice compared to non-transgenic littermates, whereas nuclear alpha-synuclein phosphorylated at Ser129 site could be linked to early pathology and metabolic dysfunction. The proposed and validated non-invasive high-resolution imaging tool to study oxygen saturation in the spinal cord of PD mice holds promise for assessing early changes preceding motor deficits in PD mice.

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Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson’s diseasein vivo

Cited by 3 publications

References 70 publications

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein

Imaging increased metabolism in the spinal cord in mice after middle cerebral artery occlusion

Spinal cord perfusion impairments in the M83 mouse model of Parkinson’s disease

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