The conversion of endogenous alpha-synuclein (asyn) to pathological asyn-enriched aggregates is a hallmark of Parkinson’s disease (PD). These inclusions can be detected in the central and enteric ...nervous system (ENS). Moreover, gastrointestinal symptoms can appear up to 20 years before the diagnosis of PD. The dual-hit hypothesis posits that pathological asyn aggregation starts in the ENS, and retrogradely spreads to the brain. In this study, we tested this hypothesis by directly injecting preformed asyn fibrils into the duodenum wall of wild-type rats and transgenic rats with excess levels of human asyn. We provide a meticulous characterization of the bacterial artificial chromosome (BAC) transgenic rat model with respect to initial propagation of pathological asyn along the parasympathetic and sympathetic pathways to the brainstem, by performing immunohistochemistry at early time points post-injection. Induced pathology was observed in all key structures along the sympathetic and parasympathetic pathways (ENS, autonomic ganglia, intermediolateral nucleus of the spinal cord (IML), heart, dorsal motor nucleus of the vagus, and locus coeruleus (LC)) and persisted for at least 4 months post-injection. In contrast, asyn propagation was not detected in wild-type rats, nor in vehicle-injected BAC rats. The presence of pathology in the IML, LC, and heart indicate
trans
-synaptic spread of the pathology. Additionally, the observed asyn inclusions in the stomach and heart may indicate secondary anterograde propagation after initial retrograde spreading. In summary,
trans
-synaptic propagation of asyn in the BAC rat model is fully compatible with the “body-first hypothesis” of PD etiopathogenesis. To our knowledge, this is the first animal model evidence of asyn propagation to the heart, and the first indication of bidirectional asyn propagation via the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The BAC rat model could be very valuable for detailed mechanistic studies of the dual-hit hypothesis, and for studies of disease modifying therapies targeting early pathology in the gastrointestinal tract.
Gastrointestinal infections cause significant health problems, including those affecting the immune, musculoskeletal, and nervous system, and are one of the leading causes for death worldwide. Recent ...findings suggest that microbiota of the gastrointestinal tract contribute to dementia.
In this nested case-control study we investigated the role of common gastrointestinal infections on the subsequent risk of dementia.
We used a longitudinal sample of 202,806 individuals from health claims data of the largest German health insurer and applied a nested case-control design with 23,354 initial dementia cases between 2006 and 2014 and 23,354 matched controls. We used conditional logistic regression to compute odds ratios (ORs) for dementia and corresponding 95%confidence intervals (CIs), adjusting for potential confounders.
The risk of dementia was increased in patients with recurring incidences of quarters with diagnosed gastrointestinal infections when compared to the unexposed population (one quarter: OR = 1.49, 95%CI = 1.40-1.58; two quarters: OR = 1.70, 95%CI = 1.51-1.91; three or more quarters: OR = 1.64, 95%CI = 1.40-1.93), adjusted for potential confounders.
Our findings suggest that recurring gastrointestinal infections are associated with an increased risk of subsequent dementia.
Parkinson’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-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 α-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 α-synuclein fibrils to induce neurological disease in TgM83
+/−
mice expressing the A53T mutant of human α-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of α-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 α-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 α-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 α-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 α-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 α-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.
Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative disorders which have been pathologically classified as synucleinopathies, since they ...are associated with pathognomonic deposits of misfolded alpha-synuclein in cells of the nervous system. Recently PD, DLB, and MSA were also suggested to be prion-like disorders. Much controversy exists regarding this analogy between synucleinopathies and prion diseases. Here, we discuss what characterizes prion diseases and in which way synucleinopathies may be considered prion-like or -unlike. We critically review recent clinical and in vivo evidence from transmission studies to animals in support of or questioning the prion hypothesis of human synucleinopathies. We conclude that, although PD, DLB, and MSA fulfill many criteria of prion-likeness, they also still fail some of these criteria.
Biotinylation is probably the most frequent and practically useful modification of molecules to facilitate selective and highly affine binding to (strept)avidin for immobilization, enrichment, and ...purification for further (bio)chemical or (bio)physical investigations. We present a protecting-group-free synthesis of a branched biotin bis-azide that enables dual-payload late-stage functionalization with arbitrary alkynes via click chemistry. Utility of the chassis is briefly showcased on the example of a valuable Pittsburgh B analogue, which binds pathological protein aggregates, commonly found in neurodegenerative diseases.
Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson's disease. Braak and colleagues have hypothesized that the initial formation ...of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson's disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson's disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson's disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson's disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.
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.
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