Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity

Yen, Chi-Fu; Harischandra, Dilshan S.; Kanthasamy, Anumantha G.; Sivasankar, Sanjeevi

doi:10.1126/sciadv.1600014

Cited by 47 publications

(40 citation statements)

References 78 publications

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“…As a consequence, structural sub-populations—including intermediates in a heterogeneous ensemble—can be distinguished and characterized directly, and the rare and/or transient states that are commonly associated with misfolding can be identified and probed 39 – 42 . Single-molecule methods have been used to study prion proteins 39 , 43 – 46 and other proteins with prion-like properties such as α-synuclein 40 , 47 – 50 and Aβ 50 , 51 , as well as to study disulfide-bond isomerization in SOD1 52 , but they have not yet been applied to study misfolding in SOD1.…”

Section: Introductionmentioning

confidence: 99%

Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories

et al. 2017

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Prion-like misfolding of superoxide dismutase 1 (SOD1) is associated with the disease ALS, but the mechanism of misfolding remains unclear, partly because misfolding is difficult to observe directly. Here we study the most misfolding-prone form of SOD1, reduced un-metallated monomers, using optical tweezers to measure unfolding and refolding of single molecules. We find that the folding is more complex than suspected, resolving numerous previously undetected intermediate states consistent with the formation of individual β-strands in the native structure. We identify a stable core of the protein that unfolds last and refolds first, and directly observe several distinct misfolded states that branch off from the native folding pathways at specific points after the formation of the stable core. Partially folded intermediates thus play a crucial role mediating between native and non-native folding. These results suggest an explanation for SOD1’s propensity for prion-like misfolding and point to possible targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories

et al. 2017

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“…The present case may well be the first report of Wilson's and Creutzfeldt-Jakob diseases co-morbidity, suggesting a possible association of copper metabolism with the pathogenesis of CJD. Several recent studies investigate the relationship of copper and prion protein and its role in the pathogenesis of the CJD which remains unclear [7][8][9]. This case sparks a new clinical interest in pursuing further research in this direction.…”

Section: Discussionmentioning

confidence: 98%

“…Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease (CJD) in humans. Sporadic and inherited prion diseases fall into the same class as Alzheimer's and Parkinson's disease, insofar that they are all associated with the accumulation of endogenous protein aggregates [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

A probable role of copper in the comorbidity in Wilson’s and Creutzfeldt-Jakob’s Diseases: a case report

Koutsouraki

Michmizos

Patsi

et al. 2020

Virol J

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Background: To the best of our knowledgedd, there is currently no case in the literature reporting the comorbidity of Wilson's and Creutzfeldt-Jakob disease (CJD), linked through copper. Case presentation: A 44-year-old male with a history of inherited Wilson's disease (hepatolenticular degeneration), which manifested as mild liver injury and psychiatric symptoms, was admitted to our department due to speech and cognitive disturbances. Upon his admission, he had motor aphasia as well as psychomotor retardation with an otherwise normal neurological examination. Laboratory tests, including liver enzymes, copper and serum ammonia were all within normal range. The brain MRI showed increased T2 signal in the caudate nuclei, attributed to copper deposition in the context of Wilson's disease. In the electroencephalogram, periodic sharp discharges were eminent, initially unilateral and then generalized. The positive 14-3-3 protein in the cerebrospinal fluid (CSF) and the new brain MRI, that demonstrated elevated DWI signal not only in the basal ganglia but also in parts of the cerebral cortex (cortical ribbon sign), all supportive of a possible CJD diagnosis. The detection of PrP Sc in the patient's CSF, using the RT-QuIC method, which has a 99.4-100% specificity for CJD, made the diagnosis of CJD highly probable. Conclusion: This is the first report of Wilson's and Creutzfeldt-Jakob diseases co-morbidity in the literature, which could evoke a possible role of copper in the pathogenesis of CJD.

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“…This effect, seen with histidine-containing wt OR units, has been ascribed to a conformational aspect of metal-binding to the OR region, where insertions impede the ability to transition from a configuration denoted "component 3" to a multivalent configuration, "component 1" [ 54 ]. Overall, an extensive literature contains complex, and sometimes contrasting, findings [ 55 – 58 ]; taken together one may surmise that the OR region has pleiotropic effects, i . e .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, and bearing in mind that mature wt PrP C is normally considered to exist a monomer, Yen et al . reported that copper-induced structural conversion of wt PrP C predisposes it for oligomerization that is associated with toxicity [ 58 ]. Thus, we arrive at opposite predictions that in the presence of copper, the OR region of the PrP(TetraH>G) allele is now susceptible to misfolding under low Cu(II) occupancy or is prevented from Cu-dependent oligomerization.…”

Section: Discussionmentioning

confidence: 99%

Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice

et al. 2017

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Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1–4, H60G, H68G, H76G, H84G, "TetraH>G" allele) or at site 5 (composed of residues His-95 and His-110; "H95G" allele) and monitored the formation of misfolded PrP in vivo. Novel transgenic mice expressing PrP(TetraH>G) at levels comparable to wild-type (wt) controls were susceptible to mouse-adapted scrapie strain RML but showed significantly prolonged incubation times. In contrast, amino acid replacement at residue 95 accelerated disease progression in corresponding PrP(H95G) mice. Neuropathological lesions in terminally ill transgenic mice were similar to scrapie-infected wt controls, but less severe. The pattern of PrPSc deposition, however, was not synaptic as seen in wt animals, but instead dense globular plaque-like accumulations of PrPSc in TgPrP(TetraH>G) mice and diffuse PrPSc deposition in (TgPrP(H95G) mice), were observed throughout all brain sections. We conclude that OR and site 5 histidine substitutions have divergent phenotypic impacts and that cis interactions between the OR region and the site 5 region modulate pathogenic outcomes by affecting the PrP globular domain.

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Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity

Abstract: Copper induces prion protein misfolding, aggregation, and neurotoxicity.

Cited by 47 publications

References 78 publications

Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories

Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories

A probable role of copper in the comorbidity in Wilson’s and Creutzfeldt-Jakob’s Diseases: a case report

Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice

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