The intriguing prion disorders

Abid, Karim; Soto, Claudio

doi:10.1007/s00018-006-6140-5

Cited by 42 publications

(43 citation statements)

References 109 publications

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“…At present, however, although there are clear indications that cholesterol-enriched microdomains (rafts) are essential for the proper folding of nascent PrPc protein, there are divergent findings regarding whether cellular cholesterol depletion or its enrichment would favour the misfolding of PrP. A number of studies have, in fact, shown a decrease of PrPsc generation by lowering the cellular cholesterol content with statins [7,19,20], while other studies produced evidence that cholesterol depletion abolishes PrP-raft association, promotes its accumulation and increases substantially its misfolding [28,29]. In addition, replication of misfolded PrP protein was reported to interfere with the raft composition by displacing raft proteins, such as Cav-1, likely leading to alterations of intracellular cholesterol trafficking and accumulation [30].…”

Section: Discussionmentioning

confidence: 99%

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

et al. 2010

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Scrapie is a prion disease for which no means of ante-mortem diagnosis is available. We recently found a relationship between cell susceptibility to scrapie and altered cholesterol homeostasis. In brains and in skin fibroblasts and peripheral blood mononuclear cells from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype, the levels of cholesterol esters were consistently higher than in tissues and cultures derived from animals with a scrapie-resistant genotype. Here we show that intracellular accumulation of cholesterol esters (CE) in fibroblasts derived from scrapie-susceptible sheep was accompanied by parallel alterations in the expression level of acyl-coenzymeA: cholesterol-acyltransferase (ACAT1) and caveolin-1 (Cav-1) that are involved in the pathways leading to intracellular cholesterol esterification and trafficking. Comparative analysis of cellular prion protein (PrPc) mRNA, showed an higher expression level in cells from animals carrying a susceptible genotype, with or without Scrapie. These data suggest that CE accumulation in peripheral cells, together with the altered expression of some proteins implicated in intracellular cholesterol homeostasis, might serve to identify a distinctive lipid metabolic profile associated with increased susceptibility to develop prion disease following infection.

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Section: Discussionmentioning

confidence: 99%

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

et al. 2010

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“…Several studies (1,9,17,32,35) have pointed out the essential role of cellular cholesterol for the proper folding and trafficking of PrPc, indicating that the conversion rate of PrPc into PrPsc may be modulated, at least in part, by cholesterolhomeostatic mechanisms. Conversely, PrPsc replication itself has been reported (34) to interfere with intracellular cholesterol metabolism and trafficking by displacing the cholesterol binding protein caveolin 1 from the membrane, thus suggesting that PrP perturbations may in turn exacerbate preexisting cholesterol alterations.…”

Section: Discussionmentioning

confidence: 99%

Antiprion Activity of Cholesterol Esterification Modulators: a Comparative Study Using Ex Vivo Sheep Fibroblasts and Lymphocytes and Mouse Neuroblastoma Cell Lines

Pani¹,

Norfo

Abete

et al. 2007

Antimicrob Agents Chemother

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Our studies on the role of cholesterol homeostasis in the pathogenesis of scrapie revealed abnormal accumulation of cholesterol esters in ex vivo peripheral blood mononuclear cells (PBMCs) and skin fibroblasts from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype compared to sheep with a resistant genotype. Similar alterations were observed in mouse neuroblastoma N2a cell lines persistently infected with mouse-adapted 22L and RML strains of scrapie that showed up to threefoldhigher cholesterol ester levels than parental N2a cells. We now report that proteinase K-resistant prion protein (PrPres)-producing cell populations of subclones from scrapie-infected cell lines were characterized by higher cholesterol ester levels than clone populations not producing PrPres. Treatments with a number of drugs known to interfere with different steps of cholesterol metabolism strongly reduced the accumulation of cholesterol esters in ex vivo PBMCs and skin fibroblasts from scrapie-affected sheep but had significantly less or no effect in their respective scrapie-resistant or uninfected counterparts. In scrapie-infected N2a cells, inhibition of cholesterol esters was associated with selective antiprion activity. Effective antiprion concentrations of cholesterol modulators (50% effective concentration [EC 50 ] range, 1.4 to 40 M) were comparable to those of antiprion reference compounds (EC 50 range, 0.6 to 10 M). These data confirm our hypothesis that abnormal accumulation of cholesterol esters may represent a biological marker of susceptibility to prion infection/replication and a novel molecular target of potential clinical importance.

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“…10 ) and the recombinant mouse prion protein recMoPrP 89-230 (ref. 11 ). We ask whether known chemical aggregators can inhibit amyloid fiber formation, whether known fibrillization inhibitors form colloidal aggregates and whether amyloid inhibition by these molecules is in fact mediated via colloidal aggregation.…”

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confidence: 99%

Small-molecule aggregates inhibit amyloid polymerization

et al. 2008

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Many amyloid inhibitors resemble molecules that form chemical aggregates, which are known to inhibit many proteins. Eight known chemical aggregators inhibited amyloid formation of the yeast and mouse prion proteins Sup35 and recMoPrP in a manner characteristic of colloidal inhibition. Similarly, three known anti-amyloid molecules inhibited β-lactamase in a detergent-dependent manner, which suggests that they too form colloidal aggregates. The colloids localized to preformed fibers and prevented new fiber formation in electron micrographs. They also blocked infection of yeast cells with Sup35 prions, which suggests that colloidal inhibition may be relevant in more biological milieus.The aggregation of proteins into amyloid fibers is associated with a growing list of diseases, including diabetes, Alzheimer's, Parkinson's, Huntington's and the prion diseases. In these disorders, proteins aggregate into long, unbranched fibers after misfolding into a β-sheet-rich conformation 1 . Though there are no approved therapies targeting amyloid formation directly, many organic molecules inhibit fibrillization in vitro [2][3][4][5][6][7] . Some, such as the chelator clioquinol (1), even have activity in vivo 4 . These results have inspired the hope of therapeutic applications for some molecules 3-5 . Curiously, many fibrillization inhibitors resemble molecules known to form promiscuous chemical aggregates. These colloidal particles are composed of small organic molecules and range in size from 50 to over 600 nm 8 . Once formed, they physically sequester proteins and inhibit enzymes nonspecifically 8,9 . Like many inhibitors of amyloid polymerization, these colloidal inhibitors are typically highly conjugated, hydrophobic and dye-like (Supplementary Table 1 online) 8,9 . A good example is the amyloid inhibitor Congo red (2), a dye that was one of the first molecules observed to exhibit colloidal inhibition 8 . The flavonoid baicalein (3), an inhibitor of α-synuclein polymerization 6 , resembles the known chemical aggregator quercetin (4), and 4,5-dianilinophthalimide (DAPH, 5), an inhibitor of Alzheimer's amyloid formation 2 , resembles the aggregator bisindoylmaleimide (6 ; Supplementary Fig. 1 online).Given that chemical aggregates function through enzyme sequestration, we wondered whether they might also sequester protein molecules from each other, thereby preventing amyloid polymerization. Here, we investigate this hypothesis in two classic amyloid-forming proteins: the yeast prion protein Sup35 (ref. 10 ) and the recombinant mouse prion protein recMoPrP 89-230 (ref. 11 ). We ask whether known chemical aggregators can inhibit amyloid fiber formation, whether known fibrillization inhibitors form colloidal aggregates and whether amyloid inhibition by these molecules is in fact mediated via colloidal aggregation.Eight known chemical aggregators and two known nonaggregators 8,9 were tested for inhibition of Sup35 fibrillization in a thioflavin T (ThT, 7) fluorescence assay. All eight inhibited Sup35 fibrillization b...

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The intriguing prion disorders

Cited by 42 publications

References 109 publications

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

ACAT-1, Cav-1 and PrP expression in scrapie susceptible and resistant sheep

Antiprion Activity of Cholesterol Esterification Modulators: a Comparative Study Using Ex Vivo Sheep Fibroblasts and Lymphocytes and Mouse Neuroblastoma Cell Lines

Small-molecule aggregates inhibit amyloid polymerization

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