ArticleActa neuropathologica communications2014
Deregulation of subcellular biometal homeostasis through loss of the metal transporter, Zip7, in a childhood neurodegenerative disorder.
Article in Acta neuropathologica communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 40 citations in OpenAlex.
- Role of zinc in health and disease.Clinical and experimental medicine · 2024Review
- Unlocking the brain's zinc code: implications for cognitive function and disease.Frontiers in biophysics · 2024Article
- The organization and function of the Golgi apparatus in dendrite development and neurological disorders.Genes & diseases · 2023Review
- Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex.International journal of molecular sciences · 2022Article
- Review
- Zinc Uptake and Storage During the Formation of the Cerebral Cortex in Mice.Molecular neurobiology · 2019Article
- Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes.Nutrients · 2019Review
- Demonstration of subcellular migration of CK2α localization from nucleus to sarco(endo)plasmic reticulum in mammalian cardiomyocytes under hyperglycemia.Molecular and cellular biochemistry · 2018Article
- Increased free ZnJournal of cellular and molecular medicine · 2018Article
- CuFrontiers in neuroscience · 2018Article
- A pathway for low zinc homeostasis that is conserved in animals and acts in parallel to the pathway for high zinc homeostasis.Nucleic acids research · 2017Article
- Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology.International journal of molecular sciences · 2017Review
- Coherent and Contradictory Facts, Feats and Fictions Associated with Metal Accumulation in Parkinson's Disease: Epicenter or Outcome, Yet a Demigod Question.Molecular neurobiology · 2017Review
- NCLs and ER: A stressful relationship.Biochimica et biophysica acta. Molecular basis of disease · 2017Review
- Identification of Cerebral Metal Ion Imbalance in the Brain of AgingFrontiers in aging neuroscience · 2017Article
- Restoration of intestinal function in an MPTP model of Parkinson's Disease.Scientific reports · 2016Article
- X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder.Chemical science · 2014Article
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20 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAberrant 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.
resultsWe 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.
conclusionsThis 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.
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