Environmental triggers of Parkinson's disease – Implications of the Braak and dual-hit hypotheses

Chen, Honglei; Wang, Keran; Scheperjans, Filip; Killinger, Bryan A.

doi:10.1016/j.nbd.2021.105601

Cited by 24 publications

(16 citation statements)

References 188 publications

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“…For substantiating neuroprotective effects with regard to cell body loss, further animal models of PD, such as viral-mediated overexpression of SNCA in the substantia nigra, are available [20]. In Thy1-aSyn mice, a second hit may be required for dopamine neuron loss, as suggested by the "multiple hit" hypotheses of PD [62,63]. The pesticide paraquat increased alpha-synuclein aggregation in Thy1-aSyn mice, but nigrostriatal dopamine cell loss was about 25%, which is similar to wild-type [64].…”

Section: Dopamine Loss and Parkinsonian Phenotypesmentioning

confidence: 99%

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

et al. 2023

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Development of neuroprotective therapeutics for Parkinson’s disease (PD) is facing a lack of translation from pre-clinical to clinical trials. One strategy for improvement is to increase predictive validity of pre-clinical studies by using extensively characterized animal models with a comprehensive set of validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features of sporadic PD, such as progressive loss of striatal dopamine, alpha-synuclein pathology, deficits in motor and non-motor functions, and elevation of inflammatory markers. Extensive work with this model by multiple laboratories over the past decade further increased confidence in its robustness and validity, especially for analyzing pathomechanisms of alpha-synuclein pathology and down-stream pathways, and for pre-clinical drug testing. Interestingly, while postnatal transgene expression is widespread in central and peripheral neurons, the extent and progression of down-stream pathology differs between brain regions, thereby replicating the characteristic selective vulnerability of neurodegenerative diseases. In-depth characterization of these readouts in conjunction with behavioral deficits has led to more informative endpoints for pre-clinical trials. Each drug tested in Thy1-aSyn line 61 enhances knowledge on how molecular targets, pathology, and functional behavioral readouts are interconnected, thereby further optimizing the platform towards predictive validity for clinical trials. Here, we present the current state of the art using Thy1-aSyn line 61 for drug target discovery, validation, and pre-clinical testing.

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Section: Dopamine Loss and Parkinsonian Phenotypesmentioning

confidence: 99%

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

et al. 2023

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“…One possible mechanism for the effect of αSN-AGs could be their ability to reduce the expression of tight junction proteins, particularly ZO1, and occludin, in hCMEC/D3 cells (Kuan et al, 2016). Additionally, a study on the intestinal epithelial barrier of Parkinson's disease (PD) patients found a decrease in occludin expression under the influence of αSN-AGs (Clairembault et al, 2015). Since it is known that the expression of these proteins directly affects BBB permeability and TEER, we can assume that the observed decrease in TEER and increase in permeability induced by αSN-AGs in our study may be attributed to the reduction in tight junction protein expression.…”

Section: Modulation Of Increase In Permeability and Decrease In Teer ...mentioning

confidence: 99%

“…Also, there is evidence that environmental factors increase the risk of PD, including toxins such as pesticides, air pollutants, metals, and smoking. According to the dual hit hypothesis, these factors may trigger inflammation and spread via gut-to-brain pathways to initiate or exacerbate the abnormal aggregation of α-synuclein (Hawkes, Del Tredici and Braak, 2009)(Chen et al ., 2022).…”

Section: Introductionmentioning

confidence: 99%

Secretome of Human Umbilical cord mesenchymal stem cells exerts protective impacts on the blood-brain barrier against alpha-synuclein aggregates using anin vitromodel

Marzookian,

Aliakbari,

Hourfar

et al. 2023

Preprint

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The blood-brain barrier (BBB) is a highly developed endothelial microvessel network extended to almost all parts of the central nervous system (CNS) that tightly seals cell-to-cell contacts and plays a critical role in maintaining CNS homeostasis. It also protects neurons from factors present in systemic circulation and prevents pathogens from entering the brain. Conversely, BBB disruption can initiate multiple pathways of nerve damage. BBB injury contributes significantly to various neurodegenerative diseases, including Parkinson's disease (PD). PD is also characterized by aggregation of the protein alpha-synuclein (αSN) to form intracellular inclusions. Recent studies have shown that due to their active secretions, mesenchymal stem cells (MSCs) can effectively relieve the severity of many neurological diseases. However, the impact of MSCs on BBB remains largely unclear. Here, we investigated the effect of Secretome extracted from MSCs on BBB when treated with toxic αSN- aggregates (αSN-AGs). For this purpose, MSCs were first isolated from Umbilical cord tissue (UC-MSC), and their secretome was collected. Then, the impact of the secretome on the cytotoxicity and inflammatory effects of αSN-AGs was examined on hCMEC/D3 cells using in vitro BBB models produced by mono- and co-culture systems. We explored the effects of αSN-AGs in the presence of UC-MSC secretome on permeability, TEER value, and cytokine/chemokine release. We found that the Secretome of UC-MSCs exerts protective effects by inhibiting the toxic effects of αSN-AGs on the BBB. These results strongly support the potential of UC-MSCs secretome for cell-free PD therapy. We also present an improved method for isolation of MSCs from umbilical cord tissue, which we hope will facilitate further studies on the use of these cells.

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“…First described in 2003, the “Braak’s hypothesis” suggests PD pathology follows a six-stage sequence during disease development that may start in the peripheral nervous system (PNS) [ 20 ]. This model is further expanded by the “dual-hit” hypothesis, as it suggests that PD may originate from environmental toxins such as air pollutants and viruses that enter through the nasal and/or GI route before spreading towards the brain via the vagus nerve [ 21 ]. Alternatively, in other patients with PD, it also has been hypothesized to originate in the central nervous system (CNS) and affect the amygdala first before spreading to the SN and PNS [ 22 ].…”

Section: Braak Stagingmentioning

confidence: 99%

Exploring the Connection Between the Gut Microbiome and Parkinson’s Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options

Chan

Ventura

Villeneuve

et al. 2022

JPD

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The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson’s disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts 100–500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms.

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Environmental triggers of Parkinson's disease – Implications of the Braak and dual-hit hypotheses

Cited by 24 publications

References 188 publications

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

Secretome of Human Umbilical cord mesenchymal stem cells exerts protective impacts on the blood-brain barrier against alpha-synuclein aggregates using anin vitromodel

Exploring the Connection Between the Gut Microbiome and Parkinson’s Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options

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