Dysregulation of autophagy in the central nervous system of sheep naturally infected with classical scrapie

López-Pérez, Óscar; Otero, Alicia; Filali, Hicham; Sanz-Rubio, David; Toivonen, Janne M.; Zaragoza, Pilar; Badiola, Juan José; Bolea, Rosa; Martín-Burriel, Inmaculada

doi:10.1038/s41598-019-38500-2

Cited by 24 publications

(27 citation statements)

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“…The severity of the disease closely correlates with the content of impaired proteins [22]. In this regard, genetically dysfunctional autophagic flux in the CNS caused in such proteinopathies, suggests a direct link between the autophagy activity and neurodegenerative conditions [23][24][25]. Different neurodegenerative disease manipulate different steps of autophagic flux illustrated in Fig.…”

Section: Relationship Between Autophagy State and Neurodegenerative Amentioning

confidence: 91%

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

et al. 2020

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The occurrence of neurodegenerative disease is increasingly raised. From physiopathological aspect, the emergence of auto-reactive antibodies against the nervous system antigens contributes to de-myelination in Multiple sclerosis (MS). These features cause the nervous system dysfunction. The follow-up of molecular alterations could give us a real-state vision about intracellular status during pathological circumstances. In this review, we focus on the autophagic response during MS progression and further understand the relationship between autophagy and MS and its modulatory effect on the MS evolution. The authors reviewed studies published on the autophagy status in neurodegenerative disease and on the autophagy modulation in MS prognosis, diagnosis, and possible therapies. The inevitable role of autophagy was shown in the early-stage progression of MS. Due to critical role of autophagy in different stage of cell activity in nervous system, the distinct role of autophagy should not be neglected in the development, pathogenesis, and treatment of MS.

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Section: Relationship Between Autophagy State and Neurodegenerative Amentioning

confidence: 91%

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

et al. 2020

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“…In fact, astrocyte reactivity resulting from activation of the unfolded protein response has been shown to be crucial in mediating prion neuropathology ( Smith et al, 2020 ). We observed p62 immunolabeling in both neuronal and glial cells in scrapie-infected sheep and mice ( Lopez-Perez et al, 2019b , 2020 ), but more studies including these cell populations are needed in order to deciphering the biological relevance of these findings.…”

Section: Autophagy In Prion Diseasesmentioning

confidence: 93%

“…Downregulation of mRNA transcripts of positive gene regulators of autophagy such as BECN1 , ATG5 , ATG9 , FBXW7 (F-box and WD repeat domain containing 7) and GAS5 (growth arrest-specific 5) has been observed in the CNS of scrapie-infected wild-type or transgenic mice and sheep naturally affected with classical scrapie ( Mok et al, 2007 ; Lopez-Perez et al, 2019b , 2020 ). These changes were associated with an impairment of autophagy at late stages of the disease, as only animals displaying clinical signs showed altered expression profiles.…”

Section: Autophagy In Prion Diseasesmentioning

confidence: 99%

“…Existing data suggest that neurons fail to recover homeostasis after exposure to PrP Sc , which ultimately leads to neuronal dysfunction and death by mechanisms that originate as a survival response to intracellular PrP Sc accumulation ( Mays and Soto, 2016 ). Indeed, many studies have identified autophagic dysregulation in TSE models ( Boellaard et al, 1989 , 1991 ; Liberski et al, 2004 ; Sikorska et al, 2004 ; Mok et al, 2007 ; Xu et al, 2012 ; Homma et al, 2014 ; Moon et al, 2016c ; Llorens et al, 2017 ; Thellung et al, 2018 ; Lopez-Perez et al, 2019a , b , 2020 ), although the casual relationship between these observations and disease pathogenesis is currently unknown. Considering the impact of autophagy in other neurodegenerative disorders ( Bursch and Ellinger, 2005 ; Rubinsztein, 2006 ), in this review we summarize, evaluate and discuss previous and recent findings concerning the role of this process, as well as the therapeutic effects of its modulation, in prion diseases.…”

Section: Introductionmentioning

confidence: 99%

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An Update on Autophagy in Prion Diseases

López-Pérez

Badiola

Bolea

et al. 2020

Front. Bioeng. Biotechnol.

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Autophagy is a dynamic intracellular mechanism involved in protein and organelle turnover through lysosomal degradation. When properly regulated, autophagy supports normal cellular and developmental processes, whereas defects in autophagic degradation have been associated with several pathologies, including prion diseases. Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurodegenerative disorders characterized by the accumulation of the pathological misfolded isoform (PrP Sc ) of the physiological cellular prion protein (PrP c ) in the central nervous system. Autophagic vacuoles have been described in experimental models of TSE and in the natural disease in humans. The precise connection of this process with prion-related neuropathology, or even whether autophagy is completely beneficial or pathogenic during neurodegeneration, is poorly understood. Thus, the biological role of autophagy in these diseases is still open to debate. During the last years, researchers have used a wide range of morphological, genetic and biochemical methods to monitor and manipulate the autophagic pathway and thus determine the specific role of this process in TSE. It has been suggested that PrP c could play a crucial role in modulating the autophagic pathway in neuronal cells, and the presence of abnormal autophagic activity has been frequently observed in several models of TSE both in vitro and in vivo , as well as in human prion diseases. Altogether, these findings suggest that autophagy is implicated in prion neuropathology and points to an impairment or failure of the process, potentially contributing to the pathogenesis of the disease. Additionally, autophagy is now emerging as a host defense response in controlling prion infection that plays a protective role by facilitating the clearance of aggregation-prone proteins accumulated within neurons. Since autophagy is one of the pathways of PrP Sc degradation, and drug-induced stimulation of autophagic flux (the dynamic process of autophagic degradation activity) produces anti-prion effects, new treatments based on its activation have been tested to develop therapeutic strategies for prion diseases. In this review, we summarize previous and recent findings concerning the role of autophagy in TSE.

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“…In scrapie models, there is a dysregulation in the expression of autophagy genes. In less affected areas of the infected brain, upregulation of LC3 proteins and expression of p62 indicates a role for autophagic machinery in PrP Sc clearance [ 140 ].…”

Section: Prion and Autophagymentioning

confidence: 99%

A New Take on Prion Protein Dynamics in Cellular Trafficking

Alves

Iglesia

Prado

et al. 2020

IJMS

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The mobility of cellular prion protein (PrPC) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrPC works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrPC is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrPC through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrPC traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.

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Dysregulation of autophagy in the central nervous system of sheep naturally infected with classical scrapie

Cited by 24 publications

References 68 publications

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

An Update on Autophagy in Prion Diseases

A New Take on Prion Protein Dynamics in Cellular Trafficking

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