Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis

Johnson, Michaela E.; Stecher, Benjamin; Labrie, Viviane; Brundin, Lena; Brundin, Patrik

doi:10.1016/j.tins.2018.09.007

Cited by 252 publications

(208 citation statements)

References 79 publications

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“…However, these peripheral seeding strategies may not be a realistic approximation of how asyn pathology actually originates and spreads in the human condition. We hypothesize that PD may start in a highly localized segment of the gastrointestinal tract, where the asyn aggregation/degradation balance is decidedly shifted toward aggregation due to the presence of local aggravating triggers such as inflammation and gut hyperpermeability or due to the stochastic formation of a particularly stable and neuroinvasive asyn strain [20, 36]. …”

Section: Introductionmentioning

confidence: 99%

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

et al. 2019

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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.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02040-w) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

et al. 2019

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“…that help triggers access the nervous system or spread the pathology within the CNS and 'aggravators', which may for instance increase alpha-synuclein spreading (48). In such a scenario, can be suggested that gastrointestinal inflammation may act as a facilitator.…”

Section: Numerous Proteases Such As Aminopeptidases Calpains and Camentioning

confidence: 99%

Tau accumulates in Crohn’s disease gut

Prigent

Chapelet

Lataillade

et al. 2020

Preprint

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A sizeable body of evidence has recently emerged to suggest that gastrointestinal inflammation might be involved in the development of Parkinson's disease. There is now strong epidemiological and genetical evidence linking Parkinson's disease to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, which is critically involved in Parkinson's disease pathophysiology, is upregulated in inflamed segments of Crohn's colon. The microtubule associated protein tau is another neuronal protein critically involved in neurodegenerative disorders but, in contrast to alpha-synuclein, no data are available about its expression and phosphorylation patterns in inflammatory bowel diseases. Here, we examined the expression levels of tau isoforms, their phosphorylation profile and truncation in colon biopsy specimens from 16 Crohn's disease and 6 ulcerative colitis patients and compared them to samples from 16 controls. Additional experiments were performed in full thickness segments of colon of 5 Crohn's disease and 5 control subjects, in primary cultures of rat enteric neurons and in Nrf2 knockout mice. Our results show the upregulation of two main human tau isoforms in the enteric nervous system in Crohn's disease but not in ulcerative colitis. This upregulation was not transcriptionally regulated but instead likely resulted from a decrease in protein clearance via an Nrf2 pathway.Our findings, which provide the first detailed characterization of tau in Crohn's disease, suggest that the key proteins involved in neurodegenerative disorders such as alpha-synuclein and tau, might also play a role in Crohn's disease.

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“…Indeed, multiple pathways and mechanisms appear to be implicated in PD pathogenesis. Thus, accumulation of misfolded proteins aggregates, mitochondrial dysfunction, oxidative stress (OS), energy failure, neuroinflammation or genetic mutations have been proposed to contribute to the onset and progression of PD [1,3,4]. Although highly effective therapies are available to relieve PD symptoms, mainly focused on reconstituting DA signaling in the surviving neurons, none of these treatments is curative since they are unable to restore the lost/degenerated DA neurons or to prevent or delay the disease progression [2,3].…”

Section: Introductionmentioning

confidence: 99%

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson’s disease based on DJ-1 deficiency

Solana-Manrique

Sanz

eacutes

et al. 2020

Preprint

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Parkinson's disease (PD) is a neurodenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta, which causes striatal dopamine deficiency. Although most PD cases are sporadic (iPD), approximately 5-10% of all patients suffer from monogenic PD forms caused by highly penetrant rare mutations segregating with the disease in families (fPD). One of the genes linked to monogenic PD is DJ-1. Mutations in DJ-1 cause autosomal recessive early-onset forms of fPD; however, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in the brains of iPD individuals. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we show that loss of DJ-1β function significantly increased the activities of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function in both PD models produces an enhancement of glycolysis. Our results also show that FDA-approved compounds such as meclizine and dimethyl fumarate, which have different clinical applications, are able to attenuate PD-related phenotypes in both models.Moreover, we found that they could exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.

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Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis

Cited by 252 publications

References 79 publications

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

Tau accumulates in Crohn’s disease gut

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson’s disease based on DJ-1 deficiency

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