metallothionein and Peripheral-Nervous-System-Diseases

Topics: Animals; Antigens, Viral, Tumor; Demyelinating Diseases; Metallothionein; Mice; Mice, Transgenic; Myelin P0 Protein; Myelin Proteins; Peripheral Nervous System Diseases; Phenotype; Schwann Cells; Simian virus 40

The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: α-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system.

Topics: Animals; Axons; Calcium Signaling; Cells, Cultured; Chemotaxis; Epidermis; Ganglia, Spinal; Growth Cones; Ligands; Low Density Lipoprotein Receptor-Related Protein-1; Low Density Lipoprotein Receptor-Related Protein-2; Male; Metallothionein; Nerve Regeneration; Nerve Tissue Proteins; Neurogenesis; Peripheral Nerves; Peripheral Nervous System Diseases; Rabbits; Rats, Sprague-Dawley; RNA Interference

Copper deficiency is a rare cause of sideroblastic anemia and neutropenia that often is not suspected clinically. The morphologic findings in bone marrow, while not pathognomonic, are sufficiently characteristic to suggest the diagnosis, leading to further testing to establish the correct diagnosis. Excess zinc ingestion is among the causes of copper deficiency. We present 3 cases of zinc-induced copper deficiency in which the diagnosis first was suggested on the basis of bone marrow examination. The first patient was a 47-year-old man with a debilitating peripheral neuropathy that had progressed during the previous 18 months, mild anemia, and severe neutropenia. The second was a 21-year-old man receiving zinc supplementation for acrodermatitis enteropathica in whom moderate normocytic anemia and neutropenia developed. The third patient was a 42-year-old man with anemia, severe neutropenia, and a peripheral neuropathy that had progressed during 8 months. The bone marrow findings in all cases suggested copper deficiency, which was confirmed by further laboratory testing and determined to be due to zinc excess. The morphologic features, clinical manifestations, differential diagnosis, and pathogenetic mechanisms are discussed.

Topics: Adult; Anemia, Sideroblastic; Biopsy; Bone Marrow; Bone Marrow Examination; Copper; Diagnosis, Differential; Humans; Male; Metallothionein; Middle Aged; Neutropenia; Peripheral Nervous System Diseases; Zinc