Pathological -Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-4283, USA.
Science (Impact Factor: 31.48). 11/2012; 338(6109):949-53. DOI: 10.1126/science.1227157
Source: PubMed

ABSTRACT Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.

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Available from: Kelvin Luk, Feb 04, 2015
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    • "Cell culture and animal model studies indicate that enhanced oligomerization and aggregation of α-syn is associated with increased cytotoxicity (Kahle et al., 2000; Masliah et al., 2000; Martin et al., 2004; Winner et al., 2011; Rockenstein et al., 2014), while α-syn oligomers have been shown to be significantly elevated in the brain lysates and cerebrospinal fluid of PD and DLB patients (Sharon et al., 2003; El-Agnaf et al., 2006; Paleologou et al., 2009; Tokuda et al., 2010; Aasly et al., 2014; Hansson et al., 2014; Parnetti et al., 2014). The significance of α-syn fibrillization in the pathobiology of synucleinopathies has been reinforced by recent data demonstrating that preformed recombinant α-syn fibrils can seed the aggregation of endogenous α-syn both in cultured wild-type mouse hippocampal neurons (Volpicelli-Daley et al., 2011) and in in vivo transgenic and wildtype mice (Luk et al., 2012b,a), even from the peripheral to the central nervous system (Sacino et al., 2014). Given the central role of α-syn in the pathogenesis of synucleinopathies , the characterization of their pathology in the brain has relied heavily on the use of α-syn antibodies (Spillantini et al., 1997; Baba et al., 1998; Croisier et al., 2006), the vast majority of which recognize both the monomeric and the aggregated forms of α-syn. "
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    ABSTRACT: α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically α-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including β-syn, γ-syn, β-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of α-syn, confirming further that they only detect α-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of α-syn oligomers in brain lysates from DLB compared to Alzheimer’s disease and control samples. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies.
    Neurobiology of Disease 04/2015; 79. DOI:10.1016/j.nbd.2015.04.009 · 5.20 Impact Factor
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    • "A particularly interesting study was also performed in neuronal-glial primary cultures showing that two different types of fibrils were taken up by cells and that the induced inclusions were similar to the original ones, suggesting propagation of a specific conformational seeding agent, similarly to prion strains (Sacino et al., 2013b). ␣-syn propagation evidences are not limited to cell models but have also been shown in vivo either in grafted animal models, where hostto-graft propagation via endocytosis has been observed, as proven by attenuation by co-injection of endocytosis inhibitors (Desplats et al., 2009; Hansen et al., 2011; Angot et al., 2012) or in inoculated animal models, where cell-to-cell transmission of aggregates was proven in neuroanatomically interconnected regions distant from the injection site (Luk et al., 2012a, 2012b; Sacino et al., 2013a; Bétemps et al., 2014). As for TSEs or A␤, tissue-to-tissue spreading has been assessed for ␣-syn as well. "
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    ABSTRACT: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting several mammalian species being Creutzfeldt-Jacob Disease (CJD) the most representative in human beings, scrapie in ovine, Bovine Spongiform Encephalopathy (BSE) in bovine and Chronic Wasting Disease (CWD) in cervids. As stated by the "protein-only hypothesis", the causal agent of TSEs is a self-propagating aberrant form of the prion protein (PrP) that through a misfolding event acquires a β-sheet rich conformation known as PrP(Sc) (from scrapie). This isoform is neurotoxic, aggregation prone and induces misfolding of native cellular PrP. Compelling evidence indicates that disease-specific protein misfolding in amyloid deposits could be shared by other disorders showing aberrant protein aggregates such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic lateral sclerosis (ALS) and systemic Amyloid A amyloidosis (AA amyloidosis). Evidences of shared mechanisms of the proteins related to each disease with prions will be reviewed through the available in vivo models. Taking prion research as reference, typical prion-like features such as seeding and propagation ability, neurotoxic species causing disease, infectivity, transmission barrier and strain evidences will be analyzed for other protein-related diseases. Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 04/2015; DOI:10.1016/j.virusres.2015.04.014 · 2.83 Impact Factor
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    • "Prions are infectious agents consisting solely of proteins and devoid of nuclei acids; these proteins are in a misfolded conformational state and tend to form oligomers that acting as a template promote the refold of the native protein, thereby leading to self propagation and spreading of the pathology [7]. Resembling this pathogenic mechanism, in PD misfolded α-SYN appears to trigger the conversion of normal endogenous α-SYN protein into its abnormal beta-sheet conformation and initiate a progressive neurodegenerative process [3] [4] [5]. The primary distinction between prion and prion-like protein is that whereas the propagation mechanisms appear to be similar in both cases, only prions are infectious. "
    Journal of the Neurological Sciences 02/2015; 351(1-2). DOI:10.1016/j.jns.2015.02.033 · 2.26 Impact Factor
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Questions & Answers about this publication

  • Nolwen Rey added an answer in alpha-Synuclein:
    What is the reason for blocking the development of pathology after fibrils injection in a-syn knock out mice?
    It seems that endocytosis is the most important factor for expansion of a-syn in brain tissue. Additionally, it seems that knock-out mice have no problem in their essential functions of the brain, so we can conclude that endocytosis is doing properly in their brain. Therefore, I think, it is interesting to know what other factors can be involved in the expansion process that are affected by the absence of endogenous a-syn? Is there any other hypothesis in this manner?
    Nolwen Rey · Van Andel Research Institute
    I assume your question is in the context of the intracerebral injection of alpha-synuclein fibrils. Some of those experiments (cited in George et al 2013) are meant to investigate the hypothesis that a misfolded form of alpha-synuclein (here the fibrils) can transmit its pathological conformation to normal alpha-synuclein (when injected into the brain), and induce a spread of synucleinopathy throughout the brain. In those experiments, SNCA KO mice are used as " controls", and it was shown that when no endogenous alpha-synuclein is present in the brain (SNCA KO mice), asyn fibrils cannot induce a spread of pathology (Luk et al. 2012, Science- see suppl. figure S6). Now regarding inflammation, the intracerebral injection by itself induces also an inflammatory response, so i think both WT mice, and SNCA mice are in a comparable state of inflammation, and this does not alter their response to fibrils injection in one mouse line or the other.