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Neuron-to-neuron transmission of ?-synuclein fibrils through axonal transport.

ABSTRACT: The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded ?-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous ?-synuclein to misfold. Here, we characterized and quantified the axonal transport of ?-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport.We grew primary cortical mouse neurons in microfluidic devices to separate somata from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent ?-synuclein fibrils and their transfer to second-order neurons.Fibrillar ?-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar ?-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts.These results support the hypothesis that the progression of Parkinson disease can be caused by neuron-to-neuron spread of ?-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be trans-synaptic gives hope that ?-synuclein fibrils could be intercepted by drugs during the extracellular phase of their journey.

SUBMITTER: Freundt EC

PROVIDER: S-EPMC3490229 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport.

Freundt Eric C EC Maynard Nate N Clancy Eileen K EK Roy Shyamali S Bousset Luc L Sourigues Yannick Y Covert Markus M Melki Ronald R Kirkegaard Karla K Brahic Michel M

Annals of neurology 20121001 4

<h4>Objective</h4>The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α-synuclein to misfold. Here, we characterized and quantified the axonal transport of α-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport.<h4> ...[more]

PMID: 23109146

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Project description:Parkinson's disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated ?-synuclein in the CNS. Disease-associated ?-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated ?-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of ?-synuclein fibrils to induce neurological disease in TgM83+/- mice expressing the A53T mutant of human ?-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of ?-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384?±?131 days, respectively. Intravenous challenge with 50 µg of ?-synuclein fibrils led to disease in 208?±?20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of ?-synuclein fibrils, which caused disease in 10 out of 10 mice in 202?±?35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of ?-synuclein fibrils developed disease in 156?±?20 days and 133?±?4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated ?-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that ?-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.

Project description:Human coronaviruses (HCoVs) are recognized respiratory pathogens for which accumulating evidence indicates that in vulnerable patients the infection can cause more severe pathologies. HCoVs are not always confined to the upper respiratory tract and can invade the central nervous system (CNS) under still unclear circumstances. HCoV-induced neuropathologies in humans are difficult to diagnose early enough to allow therapeutic interventions. Making use of our already described animal model of HCoV neuropathogenesis, we describe the route of neuropropagation from the nasal cavity to the olfactory bulb and piriform cortex and then the brain stem. We identified neuron-to-neuron propagation as one underlying mode of virus spreading in cell culture. Our data demonstrate that both passive diffusion of released viral particles and axonal transport are valid propagation strategies used by the virus. We describe for the first time the presence along axons of viral platforms whose static dynamism is reminiscent of viral assembly sites. We further reveal that HCoV OC43 modes of propagation can be modulated by selected HCoV OC43 proteins and axonal transport. Our work, therefore, identifies processes that may govern the severity and nature of HCoV OC43 neuropathogenesis and will make possible the development of therapeutic strategies to prevent occurrences.IMPORTANCE Coronaviruses may invade the CNS, disseminate, and participate in the induction of neurological diseases. Their neuropathogenicity is being increasingly recognized in humans, and the presence and persistence of human coronaviruses (HCoV) in human brains have been proposed to cause long-term sequelae. Using our mouse model relying on natural susceptibility to HCoV OC43 and neuronal cell cultures, we have defined the most relevant path taken by HCoV OC43 to access and spread to and within the CNS toward the brain stem and spinal cord and studied in cell culture the underlying modes of intercellular propagation to better understand its neuropathogenesis. Our data suggest that axonal transport governs HCoV OC43 egress in the CNS, leading to the exacerbation of neuropathogenesis. Exploiting knowledge on neuroinvasion and dissemination will enhance our ability to control viral infection within the CNS, as it will shed light on underlying mechanisms of neuropathogenesis and uncover potential druggable molecular virus-host interfaces.

Dataset Information

Neuron-to-neuron transmission of ?-synuclein fibrils through axonal transport.

Publications

Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport.

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