A new blood serum test for diagnosing neurodegenerative diseases

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Synucleinopathies are a group of neurodegenerative diseases caused by abnormal accumulation of α-synuclein, a protein normally found in the brain and neurons. Misfolding of α-synuclein leads to the formation of ‘seeds’, which attract more α-synuclein proteins to form larger clumps. Although, seed α-synuclein has been found in various tissues and blood of patients with synucleinopathies, its potential as a biomarker is still ambiguous.

Credit: Professor Hattori and his team from the University of Juntendo School of Medicine

Recently, in a study published in Natural MedicineAssociate Professor Ayami Okuzumi together with Senior Associate Professor Taku Hatano, both from the Juntendo University School of Medicine, Senior Assistant Professor Gen Matsumoto at the Nagasaki University School of Medicine, and Professor Nobutaka Hattori from the Juntendo University School of Medicine/RIKEN Center for Brain Science, presented a new test that can efficiently detect α-synuclein seeds from patient serum.

In this assay, named immunoprecipitation-based real-time earthquake-induced conversion (IP/RT-QuIC), α-synuclein seeds were isolated from patient serum via immunoprecipitation (separation of proteins using antibodies that bind only to target proteins) followed by rapid amplification by induced conversion. real time earthquake (amplification induced by strong shaking). This method is very sensitive, as it can detect serum α-synuclein seed concentrations as small as 1000pg/ml. This comes as great news because most of the existing diagnostic methods require cerebrospinal fluid for synuclein detection. Current study available/published on 30 May 2023.

Sharing their study goals, Professor Hattori and his team explained, “In this study, we validate the usability of our new test system, IP/RT-QuIC, as a diagnostic marker of synucleinopathies. We propose that the fibril morphology of serum α-synuclein seeds and aggregates derived by IP/RT-QuIC can differentiate between Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)..”

The research team demonstrated that IP/RT-QuIC detects α-synuclein seeds efficiently in patients with neurodegenerative diseases and can differentiate them from people without degenerative diseases (controls). Next, they studied the structural properties of the amplified seeds using a transmission electron microscope (TEM). They observed that the structure of the synuclein seeds varied with the type of synucleinopathy. PD and DLB seeds show paired filaments whereas MSA seeds have two distinct structures – twisted and straight filaments. These findings confirmed that IP/RT-QuIC coupled with TEM can differentiate between synucleinopathies based on disease-specific seed structure.

Subsequently, when the researchers transduced the amplified seeds into the HEK293T cell line stably expressing human α-synuclein fused to GFP with the p.A53T mutation (in vitro) and injecting the seeds into the brains of rats (life), the seeds retain their aggregate-forming capacity and disease-specific seed structures. These aggregates display different morphology depending on the type of disease. Thus, specific synucleinopathies can be diagnosed by IP/RT-QuIC from the structural differences of α-synuclein seeds and their aggregates.

This technique can help provide a quick and efficient diagnosis to patients. Professor Hattori and his team explained, “Currently, a Neurologist consultation is necessary to diagnose sinucleinopathy. However, using IP/RTQuIC, a general internist can make a diagnosis. Therefore, more patients with synucleinopathies can be diagnosed correctly and can receive appropriate treatment at an early stage.”

The authors conclude with their future vision, “Our new IP/RT-QuIC assay may have many future applications as a biomarker for the precise diagnosis and treatment monitoring of neurodegenerative diseases in clinical trials. This simple diagnostic method will allow the establishment of personalized treatment options for synucleinopathy.”

Reference

Writer	Ayami Okuzumi¹Taku Hatano¹Gene Matsumoto²Shuko Nojiri³Shin-i Ueno¹Yoko Imamichi¹Haruka Kimura¹Soichiro Kakuta⁴Akihide Kondo⁵Takeshi Fukuhara⁶yuanzhe Li¹Manabu Funayama¹Shinji Saiki¹Daisuke Taniguchi¹Taiji Tsunami¹Deborah McIntyre⁷Jean-Jacques Gerardy⁸Michel Mittelbronn⁸Rejko Krueger⁷Yasuo Uchiyama⁹Nobuyuki Nukina¹⁰and Nobutaka Hattori^{1, 6}
Original paper title	Propagative α-synuclein seeds in the sera of patients with synucleinopathies
Journal	Natural Medicine
DOI	10.1038/s41591-023-02358-9
Affiliate	¹Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan ²Department of Histology and Cell Biology, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan ³Center for Medical Technology Innovation, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan ⁴Morphological and Image Analysis Laboratory, Biomedical Research Core Facility, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan ⁵Department of Neurosurgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan ⁶Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama 351-0198, Japan ⁷Transversal Translational Medicine, Luxembourg Institute of Health (LIH); Luxembourg Hospital Center (CHL), Luxembourg; Translational Neuroscience, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg ⁸Luxembourg National Pathology Center (NCP), Laboratoire National de Sante (LNS), Dudelange, Luxembourg; Department of Cancer Research (DOCR), Luxembourg Institute of Health (LIH); Luxembourg Neuropathology Center (LCNP), Luxembourg System Biomedical Center (LCSB) Faculty of Science, Technology and Medicine (FSTM), and Department of Life Sciences and Medicine (DLSM), University (LCSB) ⁹Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan ¹⁰Laboratory of Structural Neuropathology, Graduate School of Brain Sciences, Doshisha University, Kyoto 602-8580, Japan

Additional information for EurekAlert

Last Article Publication Date	May 30, 2023
Research methods	Experimental study
Research Subjects	Humans, Animals, Cells
Conflict of Interest Statement	The authors report no conflict of interest

Funding information

This study was supported by AMED under Grant Number JP19dm0207070 (Brain Mapping by Integrated Neurotechnologies for Disease Studies) to NH, JP19dm0107156 (Strategic Research Program for Brain Sciences) to TH and AO, JP21wm0425015 (Brain Mechanisms and Integrated Technologies for Mental Health and Disease Studies ) to TH and AO, JP19ak0101112 (Research on New Drug Development) to TH and NH, JP21dk0207055 (Research and Development Grant for Dementia) to TH, and JP16dm0107140 (Brain Science Strategic Research Program) to NN; Grant Assistance for Scientific Research (21H04820 to NH, 21K07424 to TH, 19K16928 to AO, and 20K22693 to SU) from the Japan Society for the Promotion of Science; Visionary Council on the Moonshot Research and Development Program (JPMJMS2024-5 to NH) grant aid from the Committee on Research on Degenerative Diseases of the CNS, Research Planning and Policy Evaluation for Rare and Hard-to-Treat Diseases, Health Sciences, Employment, and Welfare Grants; Ministry of Health, Labor and Welfare, Japan to NH; Setsuro Fujii Memorial Osaka Foundation for Promotion of Fundamental Medical Research to TH; and Grant Assistance from Japan’s Ministry of Education, Culture, Sports, Science, and Technology (MEXT) to GMs (17K07098 and 20H05333) for Scientific Research in the Innovative Field “Multimode autophagy.” Current work is also supported by the National Center of Excellence in Research on Parkinson’s Disease (NCER-PD) funded by the Luxembourg National Research Fund (FNR; NCER13/BM/11264123) and the PEARL program (FNR; PEARL /P13/6682797 to RK and FNR and PEARL P16/BM/11192868 to MM).