Huntingtin-deficient zebrafish exhibit defects in iron utilization and development

Lumsden, Amanda L.; Henshall, Tanya L.; Dayan, Sonia; Lardelli, Michael; Richards, Robert I.

doi:10.1093/hmg/ddm138

Cited by 143 publications

(121 citation statements)

References 109 publications

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“…Relevant to the present findings is the observation that huntingtin has been implicated in cellular iron acquisition and utilization (3,5,61,86,91). Patients with Huntington's disease often demonstrate abnormalities of iron homeostasis, including decreased serum ferritin, increased brain ferritin, increased transferritin receptor, and decreased iron-requiring enzymes (3,5,13,86,91).…”

Section: Strategy For Identifying Novel Mg 2؉ Transporterssupporting

confidence: 54%

“…It is appealing to speculate that the expanded poly(Q) tract alters huntingtin binding with its associated proteins, so that endocytic vesicle trafficking of HIP14 is abnormal, leading to aberrant release or accumulation of divalent cations into these organelles. This notion has gained some support from studies using various cell and animal models (35,86,91,153,173). Given the pleiotropic nature of huntingtin functions, it is unlikely that altered cation transport is the sole cause of Huntington's disease, but a clearer picture of HIP14 physiology should increase our understanding of the disease progression.…”

Section: Strategy For Identifying Novel Mg 2؉ Transportersmentioning

confidence: 99%

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Molecular identification of ancient and modern mammalian magnesium transporters

Quamme

2010

American Journal of Physiology-Cell Physiology

172

182

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handling is poorly understood.The purpose of this review is to describe some of the recent insights into the identification and function of mammalian Mg 2ϩ transporters. There is a large body of physiological evidence for mammalian Mg 2ϩ transporters, which have only begun to be identified on the molecular level (11, 51,109,117,135,148,170). In particular, I will detail, at some length, the novel Mg 2ϩ transporters that have been identified over the last several years. These will be examined from the perspective of the established and more characterized mammalian Mg 2ϩ channels, mitochondrial Mrs2 and TRPM7/6. I will briefly review plant, bacterial, and yeast transporters as they relate to our newly identified mammalian Mg 2ϩ transporters, because some of these proteins share characteristics with the more ancient forms of transporters. The identification and characterization of plant, prokaryote, and yeast Mg 2ϩ transporters have been extensively reviewed elsewhere (35, 70, 73, 138).

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Section: Strategy For Identifying Novel Mg 2؉ Transporterssupporting

confidence: 54%

Section: Strategy For Identifying Novel Mg 2؉ Transportersmentioning

confidence: 99%

Molecular identification of ancient and modern mammalian magnesium transporters

Quamme

2010

American Journal of Physiology-Cell Physiology

172

182

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“…However, insights from our studies may be relevant to PD and other neurodegenerative diseases characterized by disrupted iron homeostasis. Decreased activity of TFR1 may contribute to neurodegeneration in Huntington's disease (78). Creuztfeldt-Jakob disease was recently reported to involve neuronal iron deficiency, apparently due to sequestration of the iron storage protein ferritin in prion aggregates (79).…”

Section: Resultsmentioning

confidence: 99%

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Matak

Moustafa

et al. 2016

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

107

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Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.iron | transferrin receptor | ferroportin | dopaminergic neuron | neurodegeneration

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“…For example, in zebrafish loss of HTT function is associated with a defect in iron metabolism, which at present is mechanistically unclear. A defect in selective autophagic clearance of the ironbinding protein ferritin (ferritinophagy) with loss of HTT function in HD patients and mice may therefore reflect an impairment in ferritinophagy (13,44,45). Both mutant HTT expression and HTT knockdown are found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7)(8)(9)12), consistent with a loss of Atg11/Atg23-like membrane trafficking.…”

Section: Discussionmentioning

confidence: 96%

“…Drosophila HTT expression in mouse cells treated with mouse Htt siRNA can compensate for the loss of mouse HTT, demonstrating functional conservation of the mitotic spindle and axonal transport roles of HTT from these widely divergent species (11,12). In zebrafish, depletion of HTT produces symptoms of cellular iron deficiency, showing a requirement for HTT in cellular iron utilization (13), whereas knockout of HTT in Dictyostelium discoideum demonstrates it is needed for survival when nutrients are limiting (14).…”

mentioning

confidence: 99%

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

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

258

228

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Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvationinduced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.rodegenerative disorder caused by an expansion of a CAG trinucleotide repeat encoding a polyglutamine (polyQ) tract near the N terminus of the 350-kD Huntingtin protein (HTT) (1). Identifying the normal biological function of the HTT protein is important in the effort to design and implement effective therapeutic interventions for HD, but has proved challenging.In the mouse, loss of HTT leads to lethality during gastrulation at embryonic day 7 (2-4). Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7-9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.In contrast to the embryonic lethality observed in the mouse, Drosophila lacking the endogenous Htt gene develop normally. However, adult Drosophila HTT loss-of-function (LOF) flies show an accelerated neurodege...

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Huntingtin-deficient zebrafish exhibit defects in iron utilization and development

Cited by 143 publications

References 109 publications

Molecular identification of ancient and modern mammalian magnesium transporters

Molecular identification of ancient and modern mammalian magnesium transporters

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Potential function for the Huntingtin protein as a scaffold for selective autophagy

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