In Search of Effective Treatments Targeting α-Synuclein Toxicity in Synucleinopathies: Pros and Cons

Fouka, Maria; Mavroeidi, Panagiota; Tsaka, Grigoria; Xilouri, Maria

doi:10.3389/fcell.2020.559791

Cited by 17 publications

(14 citation statements)

References 519 publications

(622 reference statements)

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“…3a, b). Pathological aggregation of α-synuclein is a pathological hallmark of Parkinson's Disease (PD), multiple system atrophy and dementia with Lewy bodies 29 . Strikingly, we found that the levels of α-synuclein were elevated in the hippocampal and cortical neurons of Nek1 Kat2J/Kat2J mice Fig.…”

Section: Resultsmentioning

confidence: 99%

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Wang

Zou

et al. 2021

Nat Commun

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Loss-of-function mutations in NEK1 gene, which encodes a serine/threonine kinase, are involved in human developmental disorders and ALS. Here we show that NEK1 regulates retromer-mediated endosomal trafficking by phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins and cerebral proteome homeostasis to promote mitochondrial and lysosomal dysfunction and aggregation of α-synuclein. The metabolic and proteomic defects of NEK1 deficiency disrupts the integrity of blood–brain barrier (BBB) by promoting lysosomal degradation of A20, a key modulator of RIPK1, thus sensitizing cerebrovascular endothelial cells to RIPK1-dependent apoptosis and necroptosis. Genetic inactivation of RIPK1 or metabolic rescue with ketogenic diet can prevent postnatal lethality and BBB damage in NEK1 deficient mice. Inhibition of RIPK1 reduces neuroinflammation and aggregation of α-synuclein in the brains of NEK1 deficient mice. Our study identifies a molecular mechanism by which retromer trafficking and metabolism regulates cerebrovascular integrity, cerebral proteome homeostasis and RIPK1-mediated neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Wang

Zou

et al. 2021

Nat Commun

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“…The findings presented here focus on the intracellular processes occurring under pathological conditions in neurons and OLGs. The release of SYN from neurons and its transmission between neuronal and other cell types are known to drive the neurodegenerative progression called prion-like spreading ( Danzer et al, 2012 ; Henderson et al, 2019 ; Fouka et al, 2020 ); however, the intercellular transport of TPPP/p25 is less well understood. Our studies have shown that both types of human cells can uptake SYN and/or TPPP/p25 from the medium ( Tőkési et al, 2014 ; Szunyogh et al, 2015 and present studies).…”

Section: Discussionmentioning

confidence: 99%

Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models

Lehotzky

Oláh

Fekete

et al. 2021

Front. Mol. Biosci.

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The pathological association of alpha-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25) is a key factor in the etiology of synucleinopathies. In normal brains, the intrinsically disordered SYN and TPPP/p25 are not found together but exist separately in neurons and oligodendrocytes, respectively; in pathological states, however, they are found in both cell types due to their cell-to-cell transmission. The autophagy degradation of the accumulated/assembled SYN has been considered as a potential therapeutic target. We have shown that the hetero-association of SYN with TPPP/p25 after their uptake from the medium by human cells (which mimics cell-to-cell transmission) inhibits both their autophagy- and the ubiquitin-proteasome system-derived elimination. These results were obtained by ELISA, Western blot, FACS and immunofluorescence confocal microscopy using human recombinant proteins and living human cells; ANOVA statistical analysis confirmed that TPPP/p25 counteracts SYN degradation by hindering the autophagy maturation at the stage of LC3B-SQSTM1/p62-derived autophagosome formation and its fusion with lysosome. Recently, fragments of TPPP/p25 that bind to the interface between the two hallmark proteins have been shown to inhibit their pathological assembly. In this work, we show that the proteolytic degradation of SYN on its own is more effective than when it is complexed with TPPP/p25. The combined strategy of TPPP/p25 fragments and proteolysis may ensure prevention and/or elimination of pathological SYN assemblies.

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“…Although most cases of PD are sporadic with a variable contribution of both environmental and genetic factors, about 10% of cases are associated with mutations in genes with autosomal dominant or recessive inheritance. SNCA which encodes the presynaptic protein α-synuclein, is arguably the most important gene linked to PD [ 122 , 123 ] and accumulating data indicate that increased expression of wild-type α-synuclein plays a crucial role in PD neurodegeneration [ 124 , 125 ].…”

Section: Trim17 and Diseasesmentioning

confidence: 99%

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death

Basu-Shrivastava

Kozoriz

Desagher

et al. 2021

Cells

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TRIM17 is a member of the TRIM family, a large class of RING-containing E3 ubiquitin-ligases. It is expressed at low levels in adult tissues, except in testis and in some brain regions. However, it can be highly induced in stress conditions which makes it a putative stress sensor required for the triggering of key cellular responses. As most TRIM members, TRIM17 can act as an E3 ubiquitin-ligase and promote the degradation by the proteasome of substrates such as the antiapoptotic protein MCL1. Intriguingly, TRIM17 can also prevent the ubiquitination of other proteins and stabilize them, by binding to other TRIM proteins and inhibiting their E3 ubiquitin-ligase activity. This duality of action confers several pivotal roles to TRIM17 in crucial cellular processes such as apoptosis, autophagy or cell division, but also in pathological conditions as diverse as Parkinson’s disease or cancer. Here, in addition to recent data that endorse this duality, we review what is currently known from public databases and the literature about TRIM17 gene regulation and expression, TRIM17 protein structure and interactions, as well as its involvement in cell physiology and human disorders.

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In Search of Effective Treatments Targeting α-Synuclein Toxicity in Synucleinopathies: Pros and Cons

Cited by 17 publications

References 519 publications

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models

To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death

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