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Pictorial representation of the neuronal pathways used in the oral routing of 263K scrapie. Initial spread (arrows) occurs in a retrograde direction along sympathetic and parasympathetic fi bers of the splanchnic and vagus nerves. Enteric and abdominal ganglia (CMCG) have an early involvement in pathogenesis.
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Although the ultimate target of infection is the central nervous system (CNS), there is evidence that the enteric nervous system (ENS) and the peripheral nervous system (PNS) are involved in the pathogenesis of orally communicated transmissible spongiform encephalopathies. In several peripherally challenged rodent models of scrapie, spread of infec...
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... hamsters, PrP C , which differs in appear- ance from the characteristic granular forms of PrP Sc (4, 5, 38, 39), was seen only in some neuronal cell bodies of the brain and the spinal cord. Staining was absent from tissues when normal serum replaced PrP antibody. Although cellular detail cannot be resolved with PET blots, aggregations of protease-resistant PrP (PrP Sc ) were seen at the same sites in all tissues and at all time points that immuno- staining was detected in adjacent ICC sections. However, in PET blots, deposits were stained more intensely by the blue- black chromogen and were more easily detected at low power than corresponding ICC-labeled deposits (Fig. 4). cuitry. Two PNS components, the cervical vagus nerve and the CMGC, were analyzed by bioassays for the presence of infec- tivity. Samples of the vagus nerve were excised from a position remote from NG to avoid the inclusion of ganglion cell bodies. The results for the vagus nerve samples are summarized in Table 2. Mortality and incubation time for the recipients in the bioassays demonstrated a low but consistent presence of infec- tivity in the cervical vagus nerve trunks. The estimated amount of infectivity was approximately 10 2 50% i.c. infective doses (ID 50i.c. ), corresponding to about 10 5 ID 50i.c. per g of tissue. Infectivity levels in the two CMGC samples (Table 3) were higher (approximately 10 3 and 10 4 ID 50i.c. ), even though the CMGC represented only a minor constituent of the homoge- nized tissue samples. Artery samples were located cranially or caudally adjacent to the CMGC. The trace levels of infectivity detected for these control specimens probably originated from residual CMGC nervous tissue. We used ICC, PET blotting, and selective infectivity assays in a time course study to determine the temporal sequence and location of scrapie infection in the ENS, splanchnic and vagal PNS, and CNS of hamsters after oral challenge with scrapie strain 263K. While bioassays provide the gold standard for detection of the scrapie agent per se, ICC and PET blot anal- yses facilitate studies on the spread of infection by using dis- ease-associated forms of PrP (pathological PrP or PrP Sc ) as surrogate markers for infectivity. A close correlation between infectivity and PrP Sc has been previously established in our animal model (2, 3). Available antibodies are unable to discriminate between host- and disease-associated forms of PrP in histologically pro- cessed tissues. We can distinguish pathological PrP from PrP C by differences in morphological appearance and distribution (4, 38, 39), but until now there was no formal proof that the disease-associated PrP detected by ICC corresponded to PrP Sc . PET blot pretreatments destroy PrP C , leaving only the protein- ase K-resistant fraction (42). Here, the deposits visualized by ICC were consistent with the PrP Sc immunostaining in adja- cent PET blots, even at early stages of incubation. These re- sults provide strong evidence that pathological PrP detected by our ICC method is PrP Sc . Based on a series of studies examining the pathogenesis of 263K scrapie after oral challenge in hamsters, we proposed that the infectious agent reaches its initial CNS target sites by spreading in a retrograde direction along autonomic PNS path- ways and ganglia supplying the viscera, i.e., along sympathetic and parasympathetic efferents of the splanchnic and vagus nerves (4, 39). Large parts of the alimentary canal, in particu- lar, the esophagus, stomach, small intestine, and ascending colon, are innervated by these two nerves (17, 21), which con- tain fi bers of autonomic (efferent) and sensory (afferent) neu- rons. With the neuroanatomy of the splanchnic and vagus nerve circuitry in mind (Fig. 1), the location, timing, and pro- gression of PrP Sc deposition revealed by this study strongly support and expand our hypothesis. PrP Sc appeared and accu- mulated in a predictable temporal sequence in speci fi c sites that accurately re fl ect the described autonomic and sensory relays. Deposition was always present in the CMGC and IML before the corresponding DRG. The same holds true with respect to the DMNV and NG. The results also show that, at least in this animal model, the ENS may be a key portal of entry for the infectious agent into the splanchnic and vagus nerve circuitry. As efferent and afferent fi bers of both vagus and splanchnic nerves contact myenteric ganglia (17, 21), these would be the most likely sites for ENS-mediated neuroinva- sion. However, infection may occur via intestinal nerve termi- nals not linked to ENS ganglia or other visceral tissues. Our fi ndings suggest that after uptake from the GI tract, the infectious agent primarily spreads by two neuroanatomical pathways: (i) along the vagus nerve to the DMNV in the brain and (ii) along the splanchnic nerve to the IML of the midtho- racic spinal cord. Intramural ganglia of the gut and the CMGC are respective intervening relay points (Fig. 5). Within the CNS, the infectious agent probably travels along interneurons and sensory afferents to the SN-NG and the DRG, respec- tively. The reproducibility and spatial precision of PrP Sc dep- osition indicate that spread is not random but occurs in a stepwise fashion along the synaptically linked neuronal popu- lations. The observations indicate that initial spread occurs in a retrograde direction along efferent motor pathways, but dual efferent and sensory spread to the brain is also a possibility. The observed pattern of spread shows striking similarities to that of conventional neurotropic viruses, such as herpes sim- plex virus type 1 (22, 34), reovirus serotype 3 isolate T3C9 (40), and pseudorabies virus (14). The most logical way for PrP Sc to spread along peripheral nerves is by established axonal transport mechanisms. Several studies have reported that scrapie spreads within the nervous system by means of axonal pathways (20, 28), and the sug- gested rate of spread (0.5 to 2 mm/day) is consistent with that of slow axonal transport (10, 29, 44). It has been claimed that PrP C can be transported in an anterograde direction along peripheral nerve axons (9), but it is not known whether PrP Sc is so transported. Transportation per se was not formally es- tablished in this study, but the evidence presented here would be compatible with this. While an abundance of PrP Sc was detected in association with cell bodies of CNS neurons or peripheral ganglia, deposition in nerves (cell processes) was minimal or undetected, even at the terminal stage of disease. The low levels of infectivity found at the end stage of disease in vagus nerves compared to those found in the brain or CMGC are a further indication that in nerve fi bers, the agent is in transit rather than being actively replicated. The study did not reveal any evidence for hematogenous spread of infection to the brain. PrP Sc was not detected early in infection at sites with an impaired blood-brain barrier, such as the area postrema (Fig. 3) or the choroid plexus. In addition, routing via the blood would not be consistent with the observed selectivity of targeting. Infection via the oral route is strongly indicated (but not formally proven) in vCJD, BSE, and natural scrapie. Disease- speci fi c PrP is found in the DMNV as a characteristic feature of both vCJD (26) and early BSE (43) infections, and spreading pathways similar to those described here have been described recently for sheep with natural scrapie (47). As the pattern of pathological PrP deposition in these nonexperimental infections closely resembles that observed in orally trans- mitted hamster scrapie, our fi ndings provided new indirect evidence that vCJD in humans, BSE in cattle, and natural scrapie in sheep were caused by ingestion of TSE agent. The fi ndings reported here for experimental 263K hamster scrapie strongly indicate that after oral challenge, infection of the CNS occurs via the splanchnic and vagus nerves. As similar patho- genic mechanisms are likely to operate in other orally acquired TSEs, this work provides baseline information about the peripheral routing of infection and a rodent model with which to study ...
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Background
The United States control program for classical ovine scrapie is based in part on the finding that infection is typically spread through exposure to shed placentas from infected ewes. Transmission from goats to sheep is less well described. A suitable rodent model for examining the effect of caprine scrapie isolates in the ovine host wil...
Citations
... The accumulation is inhibited in immunodeficiency (Kitamoto et al., 1991). The transmission of PrP TSE could also be mediated through the splanchnic and vagus nerves by retrograde transport (McBride et al., 2001). The EVs could also mediate transmission through the body since PrP TSE is localised on them, and they can pass the blood-brain barrier (Fevrier et al., 2004, Mattei et al., 2009, Kawikova and Askenase, 2015. ...
... The PrP TSE was shown to spread from the intestine to the splanchnic nerve and continue to the intermediolateral cell column and to the vagus nerve, from which it gets the dorsal motor nucleus of the vagus nerve. From these locations, it gets to the brain (McBride et al., 2001, Beekes et al., 1998. Since the PrP TSE was found in the peripheral nervous system (Groschup et al., 1996), it is possible that PrP TSE can be spread by cell-to-cell contact through nerves to the brain. ...
Prions (PrP) are the main cause of neurodegenerative diseases such as Scrapie in sheep, bovine spongiform encephalopathy, chronic wasting disease in deer, and Creutzfeldt-Jakob disease in humans. Although the cellular PrP (PrPC) is involved in many cellular processes, its precise function still needs to be discovered. The disease is caused by the accumulation of a pathological form of PrP (PrPTSE), which is caused by direct contact of PrPTSE and PrPC. PrP is anchored in the membrane by GPI and can be transmitted by cell-to-cell contact, tunnelling nanotubes, or extracellular vesicles (EVs). EV factions are divided by different biogenesis into exosomes, microvesicles, and apoptotic bodies. PrPTSE was found in exosomes and microvesicles, but these fractions were never compared to each other. The first aim of the doctoral thesis is a comparison of PrP content, prion-converting activity and infectivity in these fractions on CAD5 and N2a-PK1 cellular models of infection. We isolated a fraction of large EVs (20,000× g) and small EVs (110,000× g) by centrifugation from a conditioned medium. We characterised EVs by cryo-electron microscopy and western blot with Alix, TSG-101, CD63, CD9, and HSP70 markers. The contamination from other cellular compartments was checked by calnexin. EV fractions differed in β-1 integrin content. Small EVs were depleted, and large EVs were enriched in β-1 integrin content. Small EV fraction contained vesicles with a mean size of 79 nm, and the size of large EVs started at 100 nm. EV fraction infectivity was studied using two approaches - standardisation on the original volume of conditioned medium (OVS) and standardisation on total protein amount (TPS). The infectivity efficiency was tested by cell blot, western blot, and standard scrapie cell assay. The results show that infection by large EV yields 4× higher prion signals than small EV in OVS infection and more than 20× in TPS infection, which is consistent with the 20× higher prion converting activity in large EVs. These results were verified on the N2a-PK1-RML cell model of infection. Our data indicate that large EVs are more important in the transmission of PrPTSE than small EVs and contain more prion-converting activity.
EVs are currently tested for use in the diagnosis of various diseases, including prions. The second part of the thesis focuses on the optimisation of EV detection from the blood by flow cytometry and their diagnostic potential, which we evaluated in patients with multiple sclerosis (MS) and pre-term newborns. We isolated the EVs from the venous blood of MS patients and labelled them with antibodies against endothelial cells, platelets, leukocytes and red blood cells. EVs from pre-term newborns were isolated from cord blood, and we labelled them with antibodies against endothelial cells and platelets. Standard flow cytometry did not yield differences between MS patients and healthy blood donors nor between pre-term and in-term newborns. We have improved the sensitivity of the cytometer with an upgrade of violet side scatter. After the upgrade, we re-analysed samples from cord blood. We compared the analysis by standard blue laser and violet laser side scatter and obtained significantly correlated results. The reliable analysis of EVs from blood needs thorough optimisation of isolation protocol, labelling and detection. Still, improving cytometer sensitivity does not seem particularly critical in comparative studies of different groups.
... Although resection of these tissues is unlikely to prevent PD through debulking alpha synuclein, the GALT remains of interest as an initial interface with environmental pathogens that enter the body through nasopharyngeal and orogastric routes. For example, in variant Creutzfeldt-Jakob disease, the tonsils and other gutassociated lymphoid tissues are thought to provide a gateway for infectious prions to travel via the peripheral nervous system to the central nervous system (McBride et al., 2001;Hilton, 2005;Svensson et al., 2018). This brings us to our discussion on a possible direct connection between the gut and brain in PD: the vagus nerve. ...
... However, how exactly prions spread from the gut to the brain remains unknown. One possible theory described by McBride et al. [9] is that prions could transmit via splanchnic and vagus nerves. Other possible routes are through lymphoid tissue [10] and follicular dendritic cells [11]. ...
... In this scenario, which is definitely plausible, a histological gutonly stage of Lewy pathology may simply not exist. In support, animal studies of prion diseases, such as scrapie, show that orally ingested prions lead to the simultaneous appearance of prion pathology in the DMV and the ENS (Hoffmann et al. 2007;McBride et al. 2001;van Keulen et al. 2008). In these models, we know for certain that the disease was initiated in the gut, and that the pathology spreads predominantly via the autonomic connections, but a histological gut-only disease stage with pathology restricted to the ENS could not be identified. ...
The ultimate origin of Lewy body disorders, including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB), is still incompletely understood. Although a large number of pathogenic mechanisms have been implicated, accumulating evidence support that aggregation and neuron-to-neuron propagation of alpha-synuclein may be the core feature of these disorders. The synuclein, origin, and connectome (SOC) disease model of Lewy body disorders was recently introduced. This model is based on the hypothesis that in the majority of patients, the first alpha-synuclein pathology arises in single location and spreads from there. The most common origin sites are the enteric nervous system and the olfactory system. The SOC model predicts that gut-first pathology leads to a clinical body-first subtype characterized by prodromal autonomic symptoms and REM sleep behavior disorder. In contrast, olfactory-first pathology leads to a brain-first subtype with fewer non-motor symptoms before diagnosis. The SOC model further predicts that body-first patients are older, more commonly develop symmetric dopaminergic degeneration, and are at increased risk of dementia—compared to brain-first patients. In this review, the SOC model is explained and compared to alternative models of the pathogenesis of Lewy body disorders, including the Braak staging system, and the Unified Staging System for Lewy Body Disorders. Postmortem evidence from brain banks and clinical imaging data of dopaminergic and cardiac sympathetic loss is reviewed. It is concluded that these datasets seem to be more compatible with the SOC model than with those alternative disease models of Lewy body disorders.
... It is worth noting that the central processes of the sensory nerves terminate primarily in the nucleus of the solitary tract [NTS [32], and the sympathetic postganglionic neurons located in the superior cervical ganglion that innervate the carotid bodies are known to be synaptically linked to the sympathetic preganglionic neurons located in the intermediolateral cell column [IML] of the thoracic spinal cord., Both of these areas are known to be early sites of PrP Sc accumulation following oral inoculation [33]. Moreover, the dorsal motor nucleus of the vagus [DMNV], which lies adjacent to the NTS in the medulla and is synaptically connected to it [34], is another brainstem area known to be an early site of PrP Sc accumulation following oral inoculation [33]. ...
... Both of these areas are known to be early sites of PrP Sc accumulation following oral inoculation [33]. Moreover, the dorsal motor nucleus of the vagus [DMNV], which lies adjacent to the NTS in the medulla and is synaptically connected to it [34], is another brainstem area known to be an early site of PrP Sc accumulation following oral inoculation [33]. ...
... Thus, CBs have all the elements required for prion neuroinvasion: exposure to the infectious agent, PrP C -expressing cells and proximity to neural elements necessary for transport of prions into the CNS. Although this potential route of neuroinvasion involves the presence of prions in blood it avoids the blood brain barrier and does not utilize brain areas known to have a modified blood brain barrier, such as the area postrema or choroid plexus [33]. Omission of the primary or secondary antibody, or replacement of the primary antibody with an isotype control at the same concentration as the primary antibody resulted in a lack of staining for each of the four antibodies utilized, demonstrating the specificity of the reagents and the antibodies used in this study (Supplementary Figure S1). ...
Prion diseases are fatal neurologic disorders that can be transmitted by blood transfusion. The route for neuroinvasion following exposure to infected blood is not known. Carotid bodies (CBs) are specialized chemosensitive structures that detect the concentration of blood gasses and provide feedback for the neural control of respiration. Sensory cells of the CB are highly perfused and densely innervated by nerves that are synaptically connected to the brainstem and thoracic spinal cord, known to be areas of early prion deposition following oral infection. Given their direct exposure to blood and neural connections to central nervous system (CNS) areas involved in prion neuroinvasion, we sought to determine if there were cells in the human CB that express the cellular prion protein (PrPC), a characteristic that would support CBs serving as a route for prion neuroinvasion. We collected CBs from cadaver donor bodies and determined that mast cells located in the carotid bodies express PrPC and that these cells are in close proximity to blood vessels, nerves, and nerve terminals that are synaptically connected to the brainstem and spinal cord.
... However, the mechanisms facilitating PrP TSE spread from different regions of the body to the brain remain largely unknown. One potential route supported by immunohistochemical evidence suggests that PrP TSE undergoes retrograde transmission in vagus and splanchnic nerves (McBride et al. 2001). In addition, the molecular mechanism underlying the intercellular prion spread has been proposed to primarily involve (1) direct cell-to-cell contact (Kanu et al. 2002;Paquet et al. 2007), (2) tunnelling nanotubes (Gousset et al. 2009;Langevin et al. 2010), (3) GPI painting (Baron et al. 2002) and (4) extracellular vesicles (EVs) (Fevrier et al. 2004;Guo et al. 2016;Mattei et al. 2009;Yim et al. 2015) (Fig. 3). ...
Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrP C ) to the neurotoxic pathogenic form (PrP TSE ) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrP C is transformed to the misfolded, aggregation-prone and pathogenic PrP TSE remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrP TSE accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrP TSE transmission in PrD. This review will comprehensively discuss PrP TSE transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.
... After crossing the intestinal barrier and undergoing primary replication in lymphoid tissues, PrP Sc reaches the CNS via a process known as neuroinvasion. The infection propagates from sites in the gastrointestinal tract via the vagus and splanchnic nerves to the brainstem and spinal cord, respectively [3,4]. On reaching the CNS, PrP Sc spreads from the caudal to rostral regions, i.e., via the rostral brainstem to the cerebellum, diencephalon, and frontal cortex [5]. ...
... The medulla oblongata of scrapie-infected sheep was the region in which the greatest changes in TLR gene expression were observed ( Figure 6). In this region, the expression of TLR2, 3,4,6,7,8,9, and CD36 was significantly higher (p < 0.01) in the scrapie-infected versus control animals. In the thalamus, TLR6, MyD88, and CD36 were significantly upregulated in the scrapie-infected group (p < 0.05), while TLR2 and TLR3 displayed a tendency towards upregulation (p < 0.1). ...
Prion diseases are chronic and fatal neurodegenerative diseases characterized by the accumulation of disease-specific prion protein (PrPSc), spongiform changes, neuronal loss, and gliosis. Growing evidence shows that the neuroinflammatory response is a key component of prion diseases and contributes to neurodegeneration. Toll-like receptors (TLRs) have been proposed as important mediators of innate immune responses triggered in the central nervous system in other human neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. However, little is known about the role of TLRs in prion diseases, and their involvement in the neuropathology of natural scrapie has not been studied. We assessed the gene expression of ovine TLRs in four anatomically distinct brain regions in natural scrapie-infected sheep and evaluated the possible correlations between gene expression and the pathological hallmarks of prion disease. We observed significant changes in TLR expression in scrapie-infected sheep that correlate with the degree of spongiosis, PrPSc deposition, and gliosis in each of the regions studied. Remarkably, TLR4 was the only gene upregulated in all regions, regardless of the severity of neuropathology. In the hippocampus, we observed milder neuropathology associated with a distinct TLR gene expression profile and the presence of a peculiar microglial morphology, called rod microglia, described here for the first time in the brain of scrapie-infected sheep. The concurrence of these features suggests partial neuroprotection of the hippocampus. Finally, a comparison of the findings in naturallyinfected sheep versus an ovinized mouse model (tg338 mice) revealed distinct patterns of TLRgene expression.
... Oral inoculation of hamsters with 263K scrapie prions recapitulated many of the findings from the sheep studies where 263K PrP Sc was detected in the ENS, then in the sympathetic ganglia, thoracic spinal cord, and later in the medulla [110][111][112]. Importantly, scrapie was also observed to invade the CNS through the DMNV independent of the thoracic spinal cord pathway [113,114]. In this case, scrapie prions were hypothesized to invade the ENS, then travel through the vagal nerve parasympathetic pathway, directly invade the DMNV, and subsequently transneuronally spread throughout the CNS ( Figure 2B). ...
Prion diseases are transmissible protein misfolding disorders that occur in animals and humans where the endogenous prion protein, PrPC, undergoes a conformational change into self-templating aggregates termed PrPSc. Formation of PrPSc in the central nervous system (CNS) leads to gliosis, spongiosis, and cellular dysfunction that ultimately results in the death of the host. The spread of prions from peripheral inoculation sites to CNS structures occurs through neuroanatomical networks. While it has been established that endogenous PrPC is necessary for prion formation, and that the rate of prion spread is consistent with slow axonal transport, the mechanistic details of PrPSc transport remain elusive. Current research endeavors are primarily focused on the cellular mechanisms of prion transport associated with axons. This includes elucidating specific cell types involved, subcellular machinery, and potential cofactors present during this process.
... While oral transmission of BSE/vCJD prions to WT rodents is possible, the routes along which BSE/vCJD prions propagate prior to neuroinvasion have not been investigated in detail (Barlow and Middleton, 1990). However, oral transmission studies of scrapie prions to mice and hamsters have provided important insights regarding the routes along which PrP Sc can propagate into the CNS (Kimberlin and Walker, 1989;Beekes et al., 1996;Baldauf et al., 1997;Beekes et al., 1998;McBride and Beekes, 1999;Beekes and McBride, 2000;McBride et al., 2001). In orally infected mice and hamsters, PrP Sc was first detected in gut-associated lymphoid tissues such as the Peyer's patches and the submucosal (Meissner's) and myenteric plexuses of the ENS (Beekes and McBride, 2000;McBride et al., 2001). ...
... However, oral transmission studies of scrapie prions to mice and hamsters have provided important insights regarding the routes along which PrP Sc can propagate into the CNS (Kimberlin and Walker, 1989;Beekes et al., 1996;Baldauf et al., 1997;Beekes et al., 1998;McBride and Beekes, 1999;Beekes and McBride, 2000;McBride et al., 2001). In orally infected mice and hamsters, PrP Sc was first detected in gut-associated lymphoid tissues such as the Peyer's patches and the submucosal (Meissner's) and myenteric plexuses of the ENS (Beekes and McBride, 2000;McBride et al., 2001). After accumulation in the ENS, PrP Sc was discovered to spread along two pathways from the gut to the brain. ...
... After accumulation in the ENS, PrP Sc was discovered to spread along two pathways from the gut to the brain. In the first pathway, PrP Sc was discovered to spread from the small intestine along the parasympathetic nervous system via retrograde transport along the vagus nerve to the DMV in the brainstem (Baldauf et al., 1997;Beekes et al., 1998;McBride et al., 2001). In the second pathway, PrP Sc was transported along the sympathetic nervous system to the IML in the thoracic spinal cord. ...
In several neurodegenerative disorders, proteins that typically exhibit an α-helical structure misfold into an amyloid conformation rich in β-sheet content. Through a self-templating mechanism, these amyloids are able to induce additional protein misfolding, facilitating their propagation throughout the central nervous system. This disease mechanism was originally identified for the prion protein (PrP), which misfolds into PrPSc in a number of disorders, including variant Creutzfeldt–Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE). More recently, the prion mechanism of disease was expanded to include other proteins that rely on this self-templating mechanism to cause progressive degeneration, including α-synuclein misfolding in Parkinson’s disease (PD). Several studies now suggest that PD patients can be subcategorized based on where in the body misfolded α-synuclein originates, either the brain or the gut, similar to patients developing sporadic CJD or vCJD. In this review, we discuss the human and animal model data indicating that α-synuclein and PrPSc misfolding originates in the gut in body-first PD and vCJD, and summarize the data identifying the role of the autonomic nervous system in the gut-brain axis of both diseases.
... Another major route of prion neuroinvasion involving the entry via ENS is by retrograde transport of prions through the splanchnic nerve circuitry. This is consistent with the presence of prion aggregates in the intermediolateral columns of the thoracic spinal cord during early stages of prion infection [81,82]. This route is particularly important during neuroinvasion by BSE prions in cattle, however, analysis of CWD prion accumulation following oral infection did not detect prion deposits in the coeliac ganglion of deer. ...
The spread of chronic wasting disease (CWD) during the last six decades has resulted in cervid populations of North America where CWD has become enzootic. This insidious disease has also been reported in wild and captive cervids from other continents, threatening ecosystems, livestock and public health. These CWD “hot zones” are particularly complex given the interplay between cervid PRNP genetics, the infection biology, the strain diversity of infectious prions and the long-term environmental persistence of infectivity, which hinder eradication efforts. Here, we review different aspects of CWD including transmission mechanisms, pathogenesis, epidemiology and assessment of interspecies infection. Further understanding of these aspects could help identify “control points” that could help reduce exposure for humans and livestock and decrease CWD spread between cervids.
