Aluminum inhibits neurofilament assembly, cytoskeletal incorporation, and axonal transport. Dynamic nature of aluminum-induced perikaryal neurofilament accumulations as revealed by subunit turnover.
The mechanism by which aluminum induces formation of perikaryal neurofilament (NF) inclusions remains unclear. Aluminum treatment inhibits: 1. The incorporation of newly synthesized NF subunits into Triton-insoluble cytoskeleton of axonal neurites; 2. Their degradation and dephosphorylation; 3. Their translocation into axonal neurites. It also fosters the accumulation of phosphorylated NFs within perikarya. In the present study, we addressed the relationship among these effects. Aluminum reduced the assembly of newly synthesized NF subunits into NFs. During examination of those subunits that did assemble in the presence of aluminum, it was revealed that aluminum also interfered with transport of newly assembled NFs into axonal neurites. Similarly, a delay in axonal transport of microinjected biotinylated NF-H was observed in aluminum-treated cells. Aluminum also inhibited the incorporation of newly synthesized and microinjected subunits into the Triton-insoluble cytoskeleton within both perikarya and neurites. Once incorporated into Triton-insoluble cytoskeletons, however, biotinylated subunits were retained within perikarya of aluminum-treated cells to a greater extent than within untreated cells. Notably, these subunits were depleted in the presence and absence of aluminum within 48 h, despite the persistence of the aluminum-induced perikaryal accumulation itself, suggesting that individual NF subunits undergo turnover even within aluminum-induced perikaryal accumulations. These findings demonstrate that aluminum interferes with multiple aspects of neurofilament dynamics and furthermore leaves open the possibility that aluminum-induced perikaryal NF whorls may not represent permanent structures, but rather may require continued recruitment of cytoskeletal constituents.
Shea
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Department of Biological Sciences, University of Massachusetts at Lowell, MA 01854, USA. Thomas_Shea@uml.edu
Wheeler
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Jung
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D000535:Aluminum / Q000633:toxicity*; D001345:Autoradiography; D001370:Axonal Transport / Q000187:drug effects*; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism; D016900:Neurofilament Proteins / Q000096:biosynthesis*; D011233:Precipitin Tests; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003598:Cytoskeletal Proteins; D016900:Neurofilament Proteins; D000535:Aluminum