Propagation of pathological α-synuclein in marmoset brain.
α-Synuclein is a defining, key component of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as glial cytoplasmic inclusions in multiple system atrophy (MSA). The distribution and spreading of these pathologies are closely correlated with disease progression. Recent studies have revealed that intracerebral injection of synthetic α-synuclein fibrils or pathological α-synuclein prepared from DLB or MSA brains into wild-type or transgenic animal brains induced prion-like propagation of phosphorylated α-synuclein pathology. The common marmoset is a very small primate that is expected to be a useful model of human diseases. Here, we show that intracerebral injection of synthetic α-synuclein fibrils into adult wild-type marmoset brains (caudate nucleus and/or putamen) resulted in spreading of abundant α-synuclein pathologies, which were positive for various antibodies to α-synuclein, including phospho Ser129-specific antibody, anti-ubiquitin and anti-p62 antibodies, at three months after injection. Remarkably, robust Lewy body-like inclusions were formed in tyrosine hydroxylase (TH)-positive neurons in these marmosets, strongly suggesting the retrograde spreading of abnormal α-synuclein from striatum to substantia nigra. Moreover, a significant decrease in the numbers of TH-positive neurons was observed in the injection-side of the brain, where α-synuclein inclusions were deposited. Furthermore, most of the α-synuclein inclusions were positive for 1-fluoro-2,5-bis (3-carboxy-4-hydroxystyryl) benzene (FSB) and thioflavin-S, which are dyes widely used to visualize the presence of amyloid. Thus, injection of synthetic α-synuclein fibrils into brains of non-transgenic primates induced PD-like α-synuclein pathologies within only 3 months after injection. Finally, we provide evidence indicating that neurons with abnormal α-synuclein inclusions may be cleared by microglial cells. This is the first marmoset model for α-synuclein propagation. It should be helpful in studies to elucidate mechanisms of disease progression and in development and evaluation of disease-modifying drugs for α-synucleinopathies.
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.|Department of Biological Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan.
Aki
A
Shimozawa
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan.|Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.|Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Maiko
M
Ono
Animal Research Division, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
Daisuke
D
Takahara
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.|Department of Biological Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan.
Airi
A
Tarutani
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.|Department of Biological Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan.
Sei
S
Imura
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
Masami
M
Masuda-Suzukake
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan.
Makoto
M
Higuchi
Department of Molecular Neuroimaging, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.|Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Kazuhiko
K
Yanai
Department of Biological Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan.
Shin-Ichi
SI
Hisanaga
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan. hasegawa-ms@igakuken.or.jp.
Masato
http://orcid.org/0000-0001-7415-8159
M
Hasegawa
D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002144:Callithrix; D005260:Female; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013844:Thiazoles / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
D052160:Benzothiazoles; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D014446:Tyrosine 3-Monooxygenase
Circuits; Marmoset; Parkinson; Prion; α-synuclein