Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease

Kim, Sangjune; Kwon, Seung-Hwan; Kam, Tae In; Panicker, Nikhil; Karuppagounder, Senthilkumar S.; Lee, Saebom; Lee, Jun Hee; Kim, Wonjoong Richard; Kook, Minjee; Foss, Catherine A.; Shen, Ce; Lee, Hojae; Kulkarni, Subhash; Pasricha, Pankaj J.; Lee, Gabsang; Pomper, Martin G.; Dawson, Valina L.; Dawson, Ted M.; Ko, Han Seok

doi:10.1016/j.neuron.2019.05.035

Cited by 999 publications

(853 citation statements)

References 82 publications

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“…Such changes of the local mucosal microenvironment can trigger the overexpression and aggregation of alpha synuclein in enteric neurons . This could induce alpha synuclein–related PD pathology in the enteric nervous system with subsequent prion‐like spread to the central nervous system . Thus, even a transient peripheral trigger such as exposure to oral antibiotics could induce a self‐propelling pathophysiological cascade that leads to PD motor symptoms and a diagnosis many years later.…”

Section: Discussionmentioning

confidence: 99%

“…37 This could induce alpha synuclein-related PD pathology in the enteric nervous system with subsequent prion-like spread to the central nervous system. 38 Thus, even a transient peripheral trigger such as exposure to oral antibiotics could induce a self-propelling pathophysiological cascade that leads to PD motor symptoms and a diagnosis many years later. However, independent of the gut microbiota alterations, antibiotics can also have direct harmful effects on the gut epithelium, 39 and gut barrier dysfunction may expose the host also to other exogenic pathogens or toxins that may be linked to PD pathology.…”

Section: Discussionmentioning

confidence: 99%

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Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

2019

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Background Gut microbiota alterations have been found in prodromal and established Parkinson's disease (PD). Antibiotic exposure can have long‐term effects on the composition of human intestinal microbiota, but a potential connection between antibiotic exposure and risk of PD has not been studied previously. Objective To evaluate the impact of antibiotic exposure on the risk of PD in a nationwide, register‐based, case‐control study. Methods We identified all patients who were diagnosed with PD in Finland during the years 1998 to 2014. Information was obtained on individual purchases of orally administered antibiotics during the years 1993 to 2014. We assessed the association between prior antibiotic exposure and PD using conditional logistic regression. Results The study population consisted of 13,976 PD cases and 40,697 controls. The strongest connection with PD risk was found for oral exposure to macrolides and lincosamides (adjusted odds ratio up to 1.416; 95% confidence interval, 1.053–1.904). After correction for multiple comparisons, exposure to antianaerobics and tetracyclines 10 to 15 years before the index date, sulfonamides and trimethoprim 1 to 5 years before the index date, and antifungal medications 1 to 5 years before the index date were positively associated with PD risk. In post hoc analyses, further positive associations were found for broad‐spectrum antibiotics. Conclusions Exposure to certain types of oral antibiotics seems to be associated with an elevated risk of PD with a delay that is consistent with the proposed duration of a prodromal period. The pattern of associations supports the hypothesis that effects on gut microbiota could link antibiotics to PD, but further studies are needed to confirm this. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

2019

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“…Importantly, these global transgenic models cannot capture prodromal PD states where a-synuclein pathology is restricted to a small number of sites. Based on immunohistochemical studies in human brains, Braak and colleagues have proposed a set of six stages of increasing expansion of LP-pathology, which have been confirmed by others and may represent the most common spatiotemporal sequence of LP pathology (Kim et al, 2019;Ulusoy et al, 2013). Importantly, LP pathology in DMV is a hallmark of the earliest Braak Stage I (Braak et al, 2004) and might be associated with various degrees of cell loss (Eadie, 1963;Halliday et al, 1990;Surmeier et al, 2017).…”

Section: Discussionmentioning

confidence: 88%

“…The demonstration of a-synuclein spreading throughout neural circuits in rodent model (Luk et al, 2012;Rey et al, 2018;Ulusoy et al, 2013) provided a plausible biological mechanism in support of the Braak hypothesis. Moreover, even processes that are currently believed to occur the earliest stages including the spread from the periphery to DMV neurons where successfully modelled in rodents (Holmqvist et al, 2014;Kim et al, 2019;Ulusoy et al, 2013). However, as potential functional implications are still unknown, we expanded these prodromal models to include functional physiological studies in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

Chiu

Kovacheva

Musgrove

et al. 2019

Preprint

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No disease modifying therapy is currently available for Parkinson's disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant a-synuclein selective-overexpression mouse model of prodromal PD, we identified a cellautonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility and alters cardiac function -both clinically relevant symptoms of prodromal PD. We show for the first time a causal chain of events from a-synuclein via a biophysical dysfunction of specific neuronal populations to clinically relevant prodromal symptoms. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.

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“…For a more-in-depth comprehension of the underlying mechanisms of PD, several animal models such as toxin-based models, -synuclein genetic models, and -synuclein-aggregates injected models have been generated (6)(7)(8). The neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), and rotenone, are widely used to produce the toxin-based PD model.…”

Section: Introductionmentioning

confidence: 99%

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

Kim

Xiong

et al. 2020

Preprint

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Parkinson's disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and eventually, cognitive impairment. -Synuclein protein has been known to be the most culprit protein, but the underlying pathological mechanism still remains to be elucidated. As an effort to clarify the pathogenesis mechanism by -synuclein, various PD mouse models with -synuclein overexpression have been developed. However, the systemic analysis of protein abundance change by the overexpressed -synuclein in the whole proteome level has been still lacking. To address this issue, we established two sophisticated mouse models of PD by injecting -synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T synuclein to discover overlapping pathways, which could be altered in the two different types of PD mouse model. For more accurate quantification of mouse brain proteome, stable isotope labeling with amino acid in mammal-based quantification was implemented. As a result, we have successfully identified a total of 8,355 proteins from both of the mouse models; ~6,800 and ~7,200 proteins from -synuclein PFF injected mice and human A53T -synuclein transgenic mice, respectively. From the pathway analysis of the differentially expressed proteins in common, the complement and coagulation cascade pathway were determined as the most enriched ones. This is the first study that highlights the significance of the complement and coagulation pathway in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

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Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease

Cited by 999 publications

References 82 publications

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

Antibiotic Exposure and Risk of Parkinson's Disease in Finland: A Nationwide Case‐Control Study

α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

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