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: 33.61). 11/2012; 338(6109):949-53. DOI: 10.1126/science.1227157
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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- "Injection of recombinant tau fibrils into the hippocampus has produced entorhinal cortex pathology, whereas injection into striatum and cortex caused pathology in the substantia nigra and thalamus (Iba et al., 2013). Injection of aggregated a-synuclein into the brain of wild-type or transgenic mice that express forms of human a-synuclein has produced similar results (Luk et al., 2012aLuk et al., , 2012b Masuda-Suzukake et al., 2014, 2013 Recasens et al., 2014; Tran et al., 2014; Watts et al., 2013; Woerman et al., 2015). Inoculation studies into mice thus consistently demonstrate progressive accumulation of pathology along known anatomical networks. "
ABSTRACT: Prions derived from the prion protein (PrP) were first characterized as infectious agents that transmit pathology between individuals. However, the majority of cases of neurodegeneration caused by PrP prions occur sporadically. Proteins that self-assemble as cross-beta sheet amyloids are a defining pathological feature of infectious prion disorders and all major age-associated neurodegenerative diseases. In fact, multiple non-infectious proteins exhibit properties of template-driven self-assembly that are strikingly similar to PrP. Evidence suggests that like PrP, many proteins form aggregates that propagate between cells and convert cognate monomer into ordered assemblies. We now recognize that numerous proteins assemble into macromolecular complexes as part of normal physiology, some of which are self-amplifying. This review highlights similarities among infectious and non-infectious neurodegenerative diseases associated with prions, emphasizing the normal and pathogenic roles of higher-order protein assemblies. We propose that studies of the structural and cellular biology of pathological versus physiological aggregates will be mutually informative.
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- "develops this Syn pathology is thought to progressively spread rostrally throughout the brain, gradually affecting higher order centres with disease progression, bringing about dementia and neuropsychiatric symptoms which are synonymous with late stage PD . It has recently been suggested that the misfolding of Syn is self-propagating, spreading from neuron to neuron via a 'prion-like' mechanism  . The concept of spreading Syn pathology in PD, particularly by direct transfer of Syn between neurons suggests that there would be neuronal cell death in regions spatially nearby the SNpc, where Syn pathology in PD is most evident. "
ABSTRACT: Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependent neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.
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- "This concept of interneuronal spreading is based on Braak's observation that a-synuclein pathology in the brain propagates caudo-rostrally along axonal projections (Braak et al., 2003b). This hypothesis was further supported by the detection of a-synuclein aggregates in transplanted embryonic neurons in Parkinson's disease patients' brains (Li et al., 2008; Kordower and Brundin, 2009b), the observation of neuron-to-neuron transfer of a-synuclein in mouse brain (Desplats et al., 2009), internalization of exogenous a-synuclein fibrils and induction of neuronal a-synuclein aggregation in vitro and in vivo (Emmanouilidou et al., 2010; Nonaka et al., 2010; Volpicelli-Daley et al., 2011; Danzer et al., 2012a; Luk et al., 2012a, b; Mougenot et al., 2012). Recently, exosomes have been implicated in the dissemination of misfolded proteins in a variety of neurodegenerative disorders, including Parkinson's disease (Bellingham et al., 2012; Schneider and Simons, 2013). "
ABSTRACT: Extracellular α-synuclein has been proposed as a crucial mechanism for induction of pathological aggregate formation in previously healthy cells. In vitro, extracellular α-synuclein is partially associated with exosomal vesicles. Recently, we have provided evidence that exosomal α-synuclein is present in the central nervous system in vivo. We hypothesized that exosomal α-synuclein species from patients with α-synuclein related neurodegeneration serve as carriers for interneuronal disease transmission. We isolated exosomes from cerebrospinal fluid from patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy as a non-α-synuclein related disorder that clinically overlaps with Parkinson's disease, and neurological controls. Cerebrospinal fluid exosome numbers, α-synuclein protein content of cerebrospinal fluid exosomes and their potential to induce oligomerization of α-synuclein were analysed. The quantification of cerebrospinal fluid exosomal α-synuclein showed distinct differences between patients with Parkinson's disease and dementia with Lewy bodies. In addition, exosomal α-synuclein levels correlated with the severity of cognitive impairment in cross-sectional samples from patients with dementia with Lewy bodies. Importantly, cerebrospinal fluid exosomes derived from Parkinson's disease and dementia with Lewy bodies induce oligomerization of α-synuclein in a reporter cell line in a dose-dependent manner. Our data suggest that cerebrospinal fluid exosomes from patients with Parkinson's disease and dementia with Lewy bodies contain a pathogenic species of α-synuclein, which could initiate oligomerization of soluble α-synuclein in target cells and confer disease pathology.
Questions & Answers about this publication
- 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?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.Following