Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

Sepúlveda, Denisse; Cisternas-Olmedo, Marisol; Arcos, Javiera; Nassif, Melissa; Vidal, René L.

doi:10.3389/fnmol.2022.805087

Cited by 18 publications

(14 citation statements)

References 204 publications

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“…This release of α-syn following PFF treatment could be an effort to monitor and control intracellular levels of misfolded protein, possibly attributed to the deregulation of the ALP pathway in microglia [ 255 ]. Autophagic activity impairment and lysosome dysfunction have been previously correlated to increased release of exosomes from neuronal cells and to exosomes-mediated α-syn spread and transmission [ 21 , 237 , 256 ].…”

Section: The Diverse Roles Of Exosomes In Viral Infection and Neuroge...mentioning

confidence: 99%

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

Mysiris

Vavougios

Karamichali

et al. 2022

IJMS

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

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Section: The Diverse Roles Of Exosomes In Viral Infection and Neuroge...mentioning

confidence: 99%

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

Mysiris

Vavougios

Karamichali

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…Lysosomal pathway dysfunctions are characteristic of Parkinson’s disease. α-syn is degraded by the autophagy-lysosomal pathway and interacts with lysosomal proteins [ 27 ]. The application of α-syn in our primary culture induced a clear accumulation of lysosomes, after 72 h ( Figure 2 E,F).…”

Section: Resultsmentioning

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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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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“…It encodes a lysosomal ATPase that is suggested to be a regulator of the autophagy-lysosome pathway [ 109 ]. Consistently, ATP13A2 promotes intracellular α-synuclein accumulation by impairing lysosome exocytosis using iPSC-derived neurons from Parkinson disease patients [ 110 ]. Furthermore, ATP13A2 mutation or depletion can contribute to forms of Parkinson disease-associated neurodegeneration, since it negatively regulates another Parkinson disease-correlated gene called synaptotagmin11 (SYT11) at both transcriptional and post-translational levels, leading to mTORC1 activation and decreased levels of SYT11, which cause lysosomal dysfunction and impaired degradation of autophagosomes [ 109 ].…”

Section: Role Of Autophagy In Parkinson Diseasementioning

confidence: 96%

Autophagy and Its Association with Genetic Mutations in Parkinson Disease

Erekat

2022

Med Sci Monit

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Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1–0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).

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Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

Cited by 18 publications

References 204 publications

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

Post-COVID-19 Parkinsonism and Parkinson’s Disease Pathogenesis: The Exosomal Cargo Hypothesis

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

Autophagy and Its Association with Genetic Mutations in Parkinson Disease

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