Common therapeutic strategies for prion and Alzheimer’s diseases

Elezgarai, Saioa R.; Biasini, Emiliano

doi:10.1515/hsz-2016-0190

Cited by 5 publications

(7 citation statements)

References 83 publications

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“…Collectively, these data suggest that PrP Sc could be an inconvenient pharmacological target in prion diseases [ 22 ]. Targeting PrP C could be an alternative therapeutic strategy [ 23 , 24 ]. In fact, compounds directed against PrP C may produce the dual effect of interfering with the replication of multiple prion strains, and inhibit their neurotoxicity [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

et al. 2017

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Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrPC plays at least two roles in prion diseases, by acting as a substrate for PrPSc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrPC may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrPC may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrPC. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrPC at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrPC from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrPC, as well as in the propagation of infectious prions.

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Section: Introductionmentioning

confidence: 99%

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

et al. 2017

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“…Hyperphosphorylation of tau depends on the A␤-PrP interaction (17). Therefore, understanding the A␤-PrP pathway will open new therapeutic strategies by targeting the A␤-PrP interaction (18).…”

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confidence: 99%

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

Rösener

Gremer

Reinartz

et al. 2018

Journal of Biological Chemistry

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of β-amyloid (Aβ) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. Aβ oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the Aβ-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to Aβ oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the Aβ and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The Aβ:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four Aβ to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four Aβ units are required to form one huPrP-binding site. Of note, an Aβ-binding all-d-enantiomeric peptide, RD2D3, competed with huPrP for Aβ oligomers and interfered with Aβ-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on Aβ oligomers for Aβ-PrP interactions and have yielded an all-d-peptide-based, therapeutically promising agent that competes with PrP for these interactions.

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“…Collectively, these data challenge the concept that targeting exclusively PrP Sc replication is a convenient therapeutic strategy in prion diseases. A possible complementary approach could be to also target neurotoxic pathways mediated by PrP C . We have previously described the DBCA, a cellular assay based on the intrinsic cytotoxic effects of PrP molecules carrying mutations in the central region of the protein .…”

Section: Figurementioning

confidence: 99%

“…[7] Collectively,t hese data challenge the concept that targeting exclusivelyP rP Sc replication is ac onvenient therapeutic strategy in prion diseases.Apossible complementary approach could be to also target neurotoxic pathways mediated by PrP C . [8] We have previously described the DBCA, ac ellular assay based on the intrinsic cytotoxic effects of PrP molecules carrying mutations in the central region of the protein. [9] Multiple previouss tudies indicated that this assay is au seful tool to study PrP-mediatedn eurotoxic pathways, as well as to identify and characterize novel anti-prionc ompounds.…”

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A Small‐Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity

et al. 2017

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Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self‐replicating, misfolded isoform (PrPSc) of the cellular prion protein (PrPC). No therapies are available for these pathologies. We capitalized on previously described cell‐based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.

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Common therapeutic strategies for prion and Alzheimer’s diseases

Cited by 5 publications

References 83 publications

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein

A Small‐Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity

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