Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein depos...

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Published in:Neuron (Cambridge, Mass.) Vol. 112; no. 15; p. 2540
Main Authors: Endo, Hironobu, Ono, Maiko, Takado, Yuhei, Matsuoka, Kiwamu, Takahashi, Manami, Tagai, Kenji, Kataoka, Yuko, Hirata, Kosei, Takahata, Keisuke, Seki, Chie, Kokubo, Naomi, Fujinaga, Masayuki, Mori, Wakana, Nagai, Yuji, Mimura, Koki, Kumata, Katsushi, Kikuchi, Tatsuya, Shimozawa, Aki, Mishra, Sushil K, Yamaguchi, Yoshiki, Shimizu, Hiroshi, Kakita, Akiyoshi, Takuwa, Hiroyuki, Shinotoh, Hitoshi, Shimada, Hitoshi, Kimura, Yasuyuki, Ichise, Masanori, Suhara, Tetsuya, Minamimoto, Takafumi, Sahara, Naruhiko, Kawamura, Kazunori, Zhang, Ming-Rong, Hasegawa, Masato, Higuchi, Makoto
Format: Journal Article
Language:English
Published: United States 07.08.2024
Subjects:
dementia with Lewy bodies
propagation
mouse model
marmoset model
intravital two-photon microscopy
multiple system atrophy
PET
Parkinson’s disease
in vivo
α-synuclein
ISSN:1097-4199, 1097-4199
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Summary:Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
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ISSN:1097-4199
1097-4199
DOI:10.1016/j.neuron.2024.05.006