Oral and intravenous transmission of α-synuclein fibrils to mice

Lohmann, Stephanie; Bernis, María Eugenia; Tachu, Babila; Ziemski, Alexandra; Grigoletto, Jéssica; Tamgüney, Gültekin

doi:10.1007/s00401-019-02037-5

Cited by 65 publications

(64 citation statements)

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“…It has been shown that asyn assemblies are efficiently transported both retrogradely and anterogradely through the vagus [63][64][65]. Oral challenge as well as intra-peritoneal, intra-muscular, and intravenous injections with asyn fibrils lead to widespread asyn pathology in the CNS of transgenic mice with A53T mutations [66][67][68]. Also, oral gavage with the pesticide rotenone in wild-type mice lead to the formation of pathological asyn assemblies in the DMV and medullary preganglionic neurons of the intermediolateral column, and possibly also in the substantia nigra [69].…”

Section: Evidence From Animal Studiesmentioning

confidence: 99%

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Borghammer

Berge

2019

JPD

262

218

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Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence-reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.

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Section: Evidence From Animal Studiesmentioning

confidence: 99%

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Borghammer

Berge

2019

JPD

262

218

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“…These studies demonstrate the potential of human cell models as a platform for screening compounds that potentially mitigate the formation of α-synuclein aggregation and progression of PD. Studies showing that peripheral injection of fibrils induce Parkinson's disease phenotypes particularly support that aggregated α-synuclein can travel along connected neuron pathways [31][32][33][34]. Injection of fibrils into the duodenal and pylori muscularis layers of the gut of wild type mice expressing endogenous α-synuclein results in the formation of Lewy-like pathology to the brainstem and limbic areas that is associated with behavioral defects [32].…”

Section: Introductionmentioning

confidence: 98%

Initiation and propagation of α-synuclein aggregation in the nervous system

Hijaz

Volpicelli‐Daley

2020

Mol Neurodegeneration

181

138

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The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

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“…As discussed before, the fact that α-syn aggregates were found in human brain regions affected by the disease and that some studies, like the one conducted by Braak et al (2004) showed the presence of inclusions in peripheral organs and described an association between disease stage and Lewy pathology, led the authors to propose that αsynucleinopathies could initiate in the gut or the olfactory bulb and slowly spread to the CNS (Beach et al, 2009). This evidence and the data demonstrating the ability of α-syn to propagate from the gut and other peripheral organs in animal models (Kim S. et al, 2019;Lohmann et al, 2019) as well as the finding of LBs in grafted dopaminergic neurons in PD patients (Kordower et al, 2008;Li et al, 2008) supported the prion nature of α-syn.…”

Section: α-Syn a Prion Protein?mentioning

confidence: 95%

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

Heras‐Garvin

Stefanova

2020

Front. Synaptic Neurosci.

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Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.

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Oral and intravenous transmission of α-synuclein fibrils to mice

Cited by 65 publications

References 64 publications

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

Initiation and propagation of α-synuclein aggregation in the nervous system

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

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