Brain regions susceptible to alpha-synuclein spreading

Guo, Yanju; Xiong, Huan; Chen, Kang; Zou, Jin-Jun; Lei, Peng

doi:10.1038/s41380-021-01296-7

Cited by 34 publications

(21 citation statements)

References 196 publications

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“…Microglia, the main resident immune cells in the brain, phagocytose dead cells and help to clear misfolded α-syn aggregates in Parkinson’s disease [ 46 ]. It has been shown that microglia are also actively involved in the process of cell-to-cell transmission of α-syn through the release of exosomes [ 47 ]. Guo et al, 2020 [ 47 ] showed that α-syn aggregated microglial exosomes could induce nigrostriatal degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that microglia are also actively involved in the process of cell-to-cell transmission of α-syn through the release of exosomes [ 47 ]. Guo et al, 2020 [ 47 ] showed that α-syn aggregated microglial exosomes could induce nigrostriatal degeneration. In addition, the multiple roles of the microglia in the cell-to-cell transmission was well described by George et al, 2019 [ 48 ] showing that non-activated microglia decreased α-syn neuron-to-neuron transfer; however, when activated using LPS, neuron-to-neuron transfer was increased.…”

Section: Discussionmentioning

confidence: 99%

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Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence

Henriques¹,

Rouvière²,

Giorla³

et al. 2022

IJMS

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Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson’s disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence

Henriques¹,

Rouvière²,

Giorla³

et al. 2022

IJMS

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“…It is worth mentioning that the spreading of aggregated and phosphorylated α-syn toxic species has a crucial role in the progression of PD pathology [ 43 , 44 , 45 ]. Several mechanisms have been described to mediate the cell-to-cell transmission of pathological α-syn (trans-synaptic transmission, extra-cellular vesicles, and endocytosis) across diverse brain regions [ 46 ]. Moreover, according to the Braak hypothesis, the primary events of α-syn aggregation and spreading originate outside the brain, either in the olfactory bulb or the gastrointestinal tract, further propagating through the cranial nerves from the peripheral nervous system to the brainstem and the other vulnerable areas in the CNS (i.e., SNpc and the striatum) [ 47 , 48 , 49 ].…”

Section: Potential Neuroprotective Mechanisms Of Action Of Metforminmentioning

confidence: 99%

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Agostini

Masato

Bubacco

et al. 2021

IJMS

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Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.

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“…This propagation suggested that α-synuclein (α-Syn), tau but also huntingtin, superoxide dismutase 1, and several other proteins could move among cells, and once they reach a new cell could act as a seed by recruiting endogenous proteins, leading to the formation of larger aggregates ( Goedert et al, 2010 ; Gerson and Kayed, 2013 ; Lee and Kim, 2015 ; Morozova et al, 2015 ; Forloni et al, 2016 ; Gerson et al, 2016 ; Marrero-Winkens et al, 2020 ). This evidence stems from clinical and experimental observations of a single cell, between nearby cells, and over longer distances throughout the brain ( Klingelhoefer and Reichmann, 2015 ; Forloni et al, 2016 ; Brás and Outeiro, 2021 ; Guo et al, 2021 ) Thus PD/LBD and frontotemporal dementia can follow a propagation mechanism similar to AD or TSE although the seeding mechanism is intracellular ( Danzer et al, 2009 ). Evidence from prion proteins suggests two dissociable mechanisms: intracellular toxicity and a non-toxic mechanism of propagation ( Noble et al, 2015 ; Forloni et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Oligomeropathies, inflammation and prion protein binding

2022

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The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic β amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both β amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with β-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.

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Brain regions susceptible to alpha-synuclein spreading

Cited by 34 publications

References 196 publications

Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence

Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Oligomeropathies, inflammation and prion protein binding

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