Aggregation of neurofilaments in NF-L transfected neuronal cells: regeneration of the filamentous network by a protein kinase C inhibitor.
Cytoplasmic inclusion bodies that are accumulations of neurofilaments are the pathological hallmark of many neurodegenerative diseases and have been produced in transgenic mice by overexpression of mouse (NF-L and NF-M; light and medium chains, respectively) and human (NF-M and NF-H; medium and heavy chains, respectively) neurofilament subunits. This report describes a neuronal culture model in which human NF-L was overexpressed to produce cytoplasmic accumulations of neurofilaments within cell bodies concomitant with the collapse of the endogenous neurofilament network. Electron microscopy showed that, within accumulations, neurofilaments retained a filamentous structure. The culture model thus provides a novel system in which the effect on neurofilament accumulations of manipulating protein phosphorylation can be studied. Treatment of cells containing neurofilament accumulations with bisindolylmaleimide, a specific protein kinase C inhibitor, resulted in regeneration of the filamentous network; this effect was not due to a change in the level of transfected NF-L expression. These findings lend support to the suggestion that an impairment in the regulation of protein phosphorylation may lead to the accumulation of neurofilaments seen in neurodegenerative disease.
Carter
J E
JE
Section of Old Age Psychiatry, Institute of Psychiatry, London, England.
Gallo
J M
JM
Anderson
V E
VE
Anderton
B H
BH
Robertson
J
J
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D046911:Macromolecular Substances; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma; D016900:Neurofilament Proteins / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007211:Indoles; D046911:Macromolecular Substances; D008301:Maleimides; D016900:Neurofilament Proteins; D011994:Recombinant Proteins; C044882:neurofilament protein L; C061195:neurofilament protein M; D011493:Protein Kinase C; C088060:bisindolylmaleimide