Disruption of copper homeostasis due to a mutation of
            <i>Atp7a</i>
            delays the onset of prion disease

Siggs, Owen M.; Cruite, Justin T.; Du, Xin; Rutschmann, Sophie; Masliah, Eliezer; Beutler, Bruce; Oldstone, Michael B. A.

doi:10.1073/pnas.1211499109

Cited by 31 publications

(21 citation statements)

References 48 publications

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“…Cu 2+ and Zn 2+ induce PrP endocytosis (Pauly and Harris, 1998; Sumudhu et al, 2001), upregulate PrP expression (Bellingham et al, 2009; Varela-Nallar et al, 2006), inhibit in vitro fibril formation (Bocharova et al, 2005) and suppress PrP Sc amplification (Orem et al, 2006). Mutations in the copper transport protein Atp7a, leading to reduced brain copper content, slows prion disease progression after PrP Sc inoculation (Siggs et al, 2012). Moreover, copper, zinc and iron distribution in the mouse brain depends on PrP expression levels (Pushie et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

et al. 2013

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The cellular prion protein PrPC consists of two domains – a flexible N-terminal domain, which participates in copper and zinc regulation, and a largely helical C-terminal domain that converts to β-sheet in the course of prion disease. These two domains are thought to be fully independent and non-interacting. Compelling cellular and biophysical studies, however, suggest a higher order structure that is relevant to both PrPC function, as well as misfolding in disease. Here we identify a novel Zn2+ driven N-terminal – C-terminal tertiary interaction in PrPC. The C-terminal surface participating in this interaction carries the majority of the point mutations that confer familial prion disease. Investigation of mutant PrPs finds a systematic relationship between the type of mutation and the apparent strength of this newly identified domain structure. The novel structural features identified here suggest new mechanisms by which physiologic metal ions trigger PrPC trafficking and control prion disease.

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Section: Introductionmentioning

confidence: 99%

Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

et al. 2013

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“…As such, copper has been historically regarded as a tightly sequestered cofactor that must be buried within protein active sites to protect against reactive oxygen species generation and subsequent free radical damage chemistry. Indeed, elegant work continues to identify molecular players that maintain copper homeostasis in the brain (7,8) and related organs (9)(10)(11), and loss of this strict regulation is implicated in neurotoxic stress (12)(13)(14) and a variety of neurodegenerative and neurodevelopmental disorders including Menkes (15,16) and Wilson's (17) diseases, familial amyotrophic lateral sclerosis (18,19), Alzheimer's (6,14,(20)(21)(22) and Huntington's (23, 24) diseases, and prion-mediated encephalopathies (14,25,26).…”

mentioning

confidence: 99%

Copper is an endogenous modulator of neural circuit spontaneous activity

Dodani¹,

Firl²,

Chan³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

126

150

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For reasons that remain insufficiently understood, the brain requires among the highest levels of metals in the body for normal function. The traditional paradigm for this organ and others is that fluxes of alkali and alkaline earth metals are required for signaling, but transition metals are maintained in static, tightly bound reservoirs for metabolism and protection against oxidative stress. Here we show that copper is an endogenous modulator of spontaneous activity, a property of functional neural circuitry. Using Copper Fluor-3 (CF3), a new fluorescent Cu + sensor for one-and twophoton imaging, we show that neurons and neural tissue maintain basal stores of loosely bound copper that can be attenuated by chelation, which define a labile copper pool. Targeted disruption of these labile copper stores by acute chelation or genetic knockdown of the CTR1 (copper transporter 1) copper channel alters the spatiotemporal properties of spontaneous activity in developing hippocampal and retinal circuits. The data identify an essential role for copper neuronal function and suggest broader contributions of this transition metal to cell signaling.copper signaling | fluorescent sensor | molecular imaging | neural activity

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“…In support of these studies, disruption of copper homeostasis due to a hypomorphic mutation in ATP7A delays the onset of prion disease in mice (Siggs et al, 2012). Copper levels in the brain are reduced by 60% and the amount of the disease-causing PrP Sc is significantly lower than that of the controls.…”

Section: Functional Contribution Of Atp7a and Atp7b To Brain Copper Hmentioning

confidence: 88%

Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis

Telianidis¹,

Hung²,

Materia³

et al. 2013

Front. Aging Neurosci.

125

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Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N-terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B-deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration.

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Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease

Cited by 31 publications

References 48 publications

Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

Copper is an endogenous modulator of neural circuit spontaneous activity

Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis

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