Abstract
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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, and Lewy bodies (LBs) and Lewy neurites (LNs) are characteristic features of PD
We found that marmosets developed abundant phosphorylated α-synuclein pathologies, similar to those observed in PD/Dementia with Lewy bodies (DLB), in various brain regions, including striatum, cortex and substantia nigra, at only three months after injection
Inoculation of mouse α-synuclein fibrils into marmoset brain Marmoset α-synuclein, mouse α-synuclein and human α-synuclein share 96 – 97% amino acid sequence homology (Fig 1), but marmoset and mouse α-synuclein proteins both have a threonine residue at amino acid position 53, which is an aggregation-prone mutation in familial Parkinson’s disease [41]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, and Lewy bodies (LBs) and Lewy neurites (LNs) are characteristic features of PD. The discovery of disease-associated mutation in the α-synuclein gene SNCA and subsequent immunostaining studies with antibodies demonstrated that α-synuclein is the major component of LBs and LNs [2, 55, 56]. The spreading of pathological α-synuclein is closely correlated with disease progression; the distribution pattern and spread of the pathologies are useful for disease staging of sporadic PD [3, 48]. These results suggest that intracellular amyloid-like α-synuclein fibrils can cause PD and DLB, and spreading of α-synuclein pathology in the brain is considered to be the underlying mechanism of progression of these diseases. It was experimentally demonstrated that intracerebral injection of synthetic α-synuclein fibrils and/or insoluble α-synuclein from diseased brain converts normal α-synuclein into an abnormal form, and the abnormal α-synuclein propagates throughout the brain in a prion-like manner in WT mouse [30, 33, 34, 57], α-synuclein transgenic mouse [31, 36, 60] and monkey [44]
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