Journal article

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

Alexandra Grubman, Grace E 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



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 mechanis..

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Funding Acknowledgements

We thank Dr Sara Mole and Sophia Kleine Holthaus, University College, London, for the CLN6 antibody; Professor David Palmer, Faculty of Agriculture and Life Sciences, Lincoln University, New Zealand for the CLN6 affected South Hampshire samples and Dr. Susan Piripi for assisting in collection of Merino samples. Cellomics neurite growth experiments were performed at the MHTP High Content Screening Centre with the assistance of Dr. Trevor Wilson. This work was supported by The Sigrid Juselius Foundation, the Academy of Finland, the Australian Research Council (ARC), and the National Health and Medical Research Council of Australia (NHMRC). ARW is a recipient of an ARC Future Fellowship. The funding sources had no influence in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.