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

• Published in: Acta neuropathologica communications Vol. 2; no. 1; p. 25
• Main Authors: Grubman, Alexandra, Lidgerwood, Grace E, 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 28.02.2014; BioMed Central
• Subjects: Age Factors; Alkaline Phosphatase - metabolism; Analysis; Animals; Astrocytes - enzymology; Biological Transport - genetics; Biotechnology industry; Cation Transport Proteins - deficiency; Cation Transport Proteins - genetics; Cells, Cultured; Dipeptides - pharmacology; Disease Models, Animal; Embryo, Mammalian; Genetic aspects; Homeopathy; Homeostasis - genetics; Humans; Materia medica and therapeutics; Medical research; Medicine, Experimental; Membrane Proteins - genetics; Metals - metabolism; Mice; Mice, Transgenic; Mutation - genetics; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurons; Physiological aspects; Sheep; Therapeutics; Tropomyosin - pharmacology; Up-Regulation - drug effects; Up-Regulation - genetics; Zinc - pharmacology; United States
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/2051-5960-2-25

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. 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. 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.