Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder

Alexandra Grubman, Grace Lidgerwood, Clare Duncan, Laura Bica, Jiang Li Tan, Sarah J. Parker, Aphrodite Caragounis, Jodi Meyerowitz, Irene Volitakis, Diane Moujalled, Jeffrey R. Liddell, James L. Hickey, Malcolm Horne, Shoshanah Longmuir, Jari Koistinaho, Paul S. Donnelly, Peter J. Crouch, Imke Tammen, Anthony R White, Katja M. Kanninen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND: Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.RESULTS: We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.CONCLUSIONS: This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.
Original languageEnglish
Article number25
Number of pages14
JournalActa neuropathologica communications
Volume2
DOIs
Publication statusPublished - 28 Feb 2014
Externally publishedYes

Keywords

  • Biometal homeostasis
  • Neurodegeneration
  • Zip7
  • Neuronal ceroid lipofuscinoses
  • CLN6

Cite this

Grubman, Alexandra ; Lidgerwood, Grace ; Duncan, Clare ; Bica, Laura ; Tan, Jiang Li ; Parker, Sarah J. ; Caragounis, Aphrodite ; Meyerowitz, Jodi ; Volitakis, Irene ; Moujalled, Diane ; Liddell, Jeffrey R. ; Hickey, James L. ; Horne, Malcolm ; Longmuir, Shoshanah ; Koistinaho, Jari ; Donnelly, Paul S. ; Crouch, Peter J. ; Tammen, Imke ; White, Anthony R ; Kanninen, Katja M. / Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder. In: Acta neuropathologica communications. 2014 ; Vol. 2.
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title = "Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder",
abstract = "BACKGROUND: Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.RESULTS: We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.CONCLUSIONS: This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.",
keywords = "Biometal homeostasis, Neurodegeneration, Zip7, Neuronal ceroid lipofuscinoses, CLN6",
author = "Alexandra Grubman and Grace Lidgerwood and Clare Duncan and Laura Bica and Tan, {Jiang Li} and Parker, {Sarah J.} and Aphrodite Caragounis and Jodi Meyerowitz and Irene Volitakis and Diane Moujalled and Liddell, {Jeffrey R.} and Hickey, {James L.} and Malcolm Horne and Shoshanah Longmuir and Jari Koistinaho and Donnelly, {Paul S.} and Crouch, {Peter J.} and Imke Tammen and White, {Anthony R} and Kanninen, {Katja M.}",
year = "2014",
month = "2",
day = "28",
doi = "10.1186/2051-5960-2-25",
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Grubman, A, Lidgerwood, G, Duncan, C, Bica, L, Tan, JL, Parker, SJ, Caragounis, A, Meyerowitz, J, Volitakis, I, Moujalled, D, Liddell, JR, Hickey, JL, Horne, M, Longmuir, S, Koistinaho, J, Donnelly, PS, Crouch, PJ, Tammen, I, White, AR & Kanninen, KM 2014, 'Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder' Acta neuropathologica communications, vol. 2, 25. https://doi.org/10.1186/2051-5960-2-25

Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder. / Grubman, Alexandra; Lidgerwood, Grace; Duncan, Clare; Bica, Laura; Tan, Jiang Li; Parker, Sarah J.; Caragounis, Aphrodite; Meyerowitz, Jodi; Volitakis, Irene; Moujalled, Diane; Liddell, Jeffrey R.; Hickey, James L.; Horne, Malcolm; Longmuir, Shoshanah; Koistinaho, Jari; Donnelly, Paul S.; Crouch, Peter J.; Tammen, Imke; White, Anthony R; Kanninen, Katja M.

In: Acta neuropathologica communications, Vol. 2, 25, 28.02.2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder

AU - Grubman, Alexandra

AU - Lidgerwood, Grace

AU - Duncan, Clare

AU - Bica, Laura

AU - Tan, Jiang Li

AU - Parker, Sarah J.

AU - Caragounis, Aphrodite

AU - Meyerowitz, Jodi

AU - Volitakis, Irene

AU - Moujalled, Diane

AU - Liddell, Jeffrey R.

AU - Hickey, James L.

AU - Horne, Malcolm

AU - Longmuir, Shoshanah

AU - Koistinaho, Jari

AU - Donnelly, Paul S.

AU - Crouch, Peter J.

AU - Tammen, Imke

AU - White, Anthony R

AU - Kanninen, Katja M.

PY - 2014/2/28

Y1 - 2014/2/28

N2 - BACKGROUND: Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.RESULTS: We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.CONCLUSIONS: This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.

AB - BACKGROUND: Aberrant biometal metabolism is a key feature of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Metal modulating compounds are promising therapeutics for neurodegeneration, but their mechanism of action remains poorly understood. Neuronal ceroid lipofuscinoses (NCLs), caused by mutations in CLN genes, are fatal childhood neurodegenerative lysosomal storage diseases without a cure. We previously showed biometal accumulation in ovine and murine models of the CLN6 variant NCL, but the mechanism is unknown. This study extended the concept that alteration of biometal functions is involved in pathology in these disorders, and investigated molecular mechanisms underlying impaired biometal trafficking in CLN6 disease.RESULTS: We observed significant region-specific biometal accumulation and deregulation of metal trafficking pathways prior to disease onset in CLN6 affected sheep. Substantial progressive loss of the ER/Golgi-resident Zn transporter, Zip7, which colocalized with the disease-associated protein, CLN6, may contribute to the subcellular deregulation of biometal homeostasis in NCLs. Importantly, the metal-complex, ZnII(atsm), induced Zip7 upregulation, promoted Zn redistribution and restored Zn-dependent functions in primary mouse Cln6 deficient neurons and astrocytes.CONCLUSIONS: This study demonstrates the central role of the metal transporter, Zip7, in the aberrant biometal metabolism of CLN6 variants of NCL and further highlights the key contribution of deregulated biometal trafficking to the pathology of neurodegenerative diseases. Importantly, our results suggest that ZnII(atsm) may be a candidate for therapeutic trials for NCLs.

KW - Biometal homeostasis

KW - Neurodegeneration

KW - Zip7

KW - Neuronal ceroid lipofuscinoses

KW - CLN6

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U2 - 10.1186/2051-5960-2-25

DO - 10.1186/2051-5960-2-25

M3 - Article

VL - 2

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

M1 - 25

ER -