Dataset Information

Early onset prion disease from octarepeat expansion correlates with copper binding properties.

ABSTRACT: Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset age between 30 and 40 years, a difference of almost three decades. In wild-type PrP, the octarepeat domain takes up copper (Cu(2+)) and is considered essential for in vivo function. Work from our lab demonstrates that the copper coordination mode depends on the precise ratio of Cu(2+) to protein. At low Cu(2+) levels, coordination involves histidine side chains from adjacent octarepeats, whereas at high levels each repeat takes up a single copper ion through interactions with the histidine side chain and neighboring backbone amides. Here we use both octarepeat constructs and recombinant PrP to examine how copper coordination modes are influenced by octarepeat expansion. We find that there is little change in affinity or coordination mode populations for octarepeat domains with up to seven segments (three inserts). However, domains with eight or nine total repeats (four or five inserts) become energetically arrested in the multi-histidine coordination mode, as dictated by higher copper uptake capacity and also by increased binding affinity. We next pooled all published cases of human prion disease resulting from octarepeat expansion and find remarkable agreement between the sudden length-dependent change in copper coordination and onset age. Together, these findings suggest that either loss of PrP copper-dependent function or loss of copper-mediated protection against PrP polymerization makes a significant contribution to early onset prion disease.

SUBMITTER: Stevens DJ

PROVIDER: S-EPMC2663819 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early onset prion disease from octarepeat expansion correlates with copper binding properties.

Stevens Daniel J DJ Walter Eric D ED Rodríguez Abel A Draper David D Davies Paul P Brown David R DR Millhauser Glenn L GL

PLoS pathogens 20090417 4

Insertional mutations leading to expansion of the octarepeat domain of the prion protein (PrP) are directly linked to prion disease. While normal PrP has four PHGGGWGQ octapeptide segments in its flexible N-terminal domain, expanded forms may have up to nine additional octapeptide inserts. The type of prion disease segregates with the degree of expansion. With up to four extra octarepeats, the average onset age is above 60 years, whereas five to nine extra octarepeats results in an average onset ...[more]

PMID: 19381258

Similar Datasets

Project description:Copper coordination to the prion protein (PrP) has garnered considerable interest for almost 20 years, due in part to the possibility that this interaction may be part of the normal function of PrP. The most characterized form of copper binding to PrP has been Cu(2+) interaction with the conserved tandem repeats in the N-terminal domain of PrP, termed the octarepeats, with many studies focusing on single and multiple repeats of PHGGGWGQ. Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used in several previous instances to characterize the solution structure of Cu(2+) binding into the peptide backbone in the HGGG portion of the octarepeats. All previous EXAFS studies, however, have benefitted from crystallographic structure information for [Cu(II) (Ac-HGGGW-NH2)(-2H)] but have not conclusively demonstrated that the complex EXAFS spectrum represents the same coordination environment for Cu(2+) bound to the peptide backbone. Density functional structure calculations as well as full multiple scattering EXAFS curve fitting analysis are brought to bear on the predominant coordination mode for Cu(2+) with the Ac-PHGGGWGQ-NH2 peptide at physiological pH, under high Cu(2+) occupancy conditions. In addition to the structure calculations, which provide a thermodynamic link to structural information, methods are also presented for extensive deconvolution of the EXAFS spectrum. We demonstrate how the EXAFS data can be analyzed to extract the maximum structural information and arrive at a structural model that is significantly improved over previous EXAFS characterizations. The EXAFS spectrum for the chemically reduced form of copper binding to the Ac-PHGGGWGQ-NH2 peptide is presented, which is best modeled as a linear two-coordinate species with a single His imidazole ligand and a water molecule. The extent of in situ photoreduction of the copper center during standard data collection is also presented, and EXAFS curve fitting of the photoreduced species reveals an intermediate structure that is similar to the Cu(2+) form with reduced coordination number.

Project description:Alzheimer's disease (AD) is the most common type of dementia and is characterized by cognitive and behavioral impairment that significantly interferes with social functioning. Over the last decade, there has been an increased interest in whether sensory deficiency may be associated with the development of AD. Notably, the relationship between hearing impairment and AD is of great relevance, but still poorly understood. In this study, we found an early-onset hearing loss in 3xTgAD and 3xTgAD/Polβ+/− mouse models. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings. Herein, we report that both 3xTgAD and 3xTgAD/Polβ+/− mice showed increased ABR thresholds between at 16 and 32 kHz at 4 weeks of age, much earlier than any AD behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/− mice than in 3xTgAD mice at 16 kHz, and DPOAE signals were also reduced, indicating that DNA damage may affect hearing impairment in AD. Poly ADP-ribosylation levels and protein expression of DNA damage markers increased significantly and NAD+ levels were reduced in the cochlea of 3xTgAD and 3xTgAD/Polβ+/− mice. Remarkably, we observed the downregulation of phosphoglycerate mutase 2 (PGAM2) in cochlea and a decrease in the number of synaptic ribbons in the presynaptic zones of inner hair cells in 3xTgAD/Polβ+/− mice. We also find that the activity of sirtuin 3 (SIRT3) is downregulated in cochlea, indicative of impaired mitochondrial function. Taken together, hearing impairment may be a potential early marker of AD. In addition, these findings provide new insights into the mechanism of the relationship between hearing dysfunction and AD and suggest that DNA damage in the cochlea can contributes to the development of early hearing loss of AD. The hearing assessment was measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) at 4 weeks of age, thereafter whole cochlea and auditory cortex tissue were collected from each mouse (WT, Polβ+/−, 3xTgAD, and 3xTgAD/Polβ+/−) and subjected to total RNA isolation to understand what metabolism-related gene expression changes in cochlea and auditory cortex.

Dataset Information

Early onset prion disease from octarepeat expansion correlates with copper binding properties.

Publications

Early onset prion disease from octarepeat expansion correlates with copper binding properties.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets