The expression of tubulin polymerization promoting protein TPPP/p25alpha is developmentally regulated in cultured rat brain oligodendrocytes and affected by proteolytic stress.
The tubulin polymerization-promoting protein (TPPP)/p25alpha was identified as a brain specific protein, is associated with microtubules (MTs) in vitro and can promote abnormal MT assembly. Furthermore it has aggregation promoting properties and is a constituent in pathological protein deposits of neurodegenerative diseases. In the brain, TPPP/p25alpha is present in myelinating oligodendrocytes. Here we show, using cultured rat brain oligodendrocytes, that TPPP/p25alpha expression is increasing during development in culture, and particularly in immature cells is associated with the centrosome. MT binding properties in oligodendrocytes are rather low, however, when MTs are disassembled by nocodazole, TPPP/p25alpha accumulates in the perinuclear region. Treatment of oligodendrocytes with the proteasomal inhibitor MG-132 (1 micaroM; 18 h) caused an increase in the amount of TPPP/p25alpha by about 40%, a decrease in its solubility, and led to the appearance of TPPP/p25alpha-positive cytoplasmic inclusions, which stained with thioflavin S and resembled inclusion bodies. Hence, it might be speculated that acute or chronic malfunction of the proteasomal degradation system, leading to the accumulation of aggregation prone proteins and the pro-aggregatory protein TPPP/p25alpha or to the aggregation of TPPP/p25alpha on its own, is causally related to the protein aggregation process in a variety of neurodegenerative diseases.
Department of Biology, Molecular Neurobiology, University of Oldenburg, Oldenburg, Germany.
Olaf
O
Goldbaum
Poul Henning
PH
Jensen
Christiane
C
Richter-Landsberg
D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D002479:Inclusion Bodies / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D009836:Oligodendroglia / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017208:Rats, Wistar; D014404:Tubulin / Q000096:biosynthesis; D050257:Tubulin Modulators / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009419:Nerve Tissue Proteins; D061988:Proteasome Inhibitors; C118136:TPPP protein, human; C539090:TPPP protein, rat; D014404:Tubulin; D050257:Tubulin Modulators; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D015739:Nocodazole