Aggresome formation in neuropathy models based on peripheral myelin protein 22 mutations.
Alterations in peripheral myelin protein 22 (PMP22) gene expression are associated with demyelinating peripheral neuropathies. Overexpression of wild type (wt) PMP22 or inhibition of proteasomal degradation lead to the formation of aggresomes, intracellular ubiquitinated PMP22 aggregates. Aggresome formation has now been observed with two mutant PMP22s, the Tr- and TrJ-PMP22 when the proteasome is inhibited. The formation of these aggresomes required intact microtubules and involved the recruitment of chaperones, including Hsp40, Hsp70, and alphaB-crystallin. Spontaneously formed ubiquitinated PMP22 aggregates were also observed in Schwann cells of homozygous TrJ mice. Significant upregulation of both the ubiquitin-proteasomal and lysosomal pathways occurred in affected nerves suggesting that two pathways of PMP22 degradation are present. Thus, the presence of aggresomes appears to be a common finding in neuropathy models of PMP22 overexpression and of some point mutations known to cause neuropathy in mice and humans.
Ryan
Mary C
MC
Department of Neurobiology, Stanford University School of Medicine, California 94305-5125, USA.
Shooter
Eric M
EM
Notterpek
Lucia
L
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002232:Carbocyanines; D002478:Cells, Cultured / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D003459:Crystallins / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008247:Lysosomes / Q000502:physiology; D046911:Macromolecular Substances; D051379:Mice; D008818:Mice, Neurologic Mutants; D008870:Microtubules / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012583:Schwann Cells / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
C091791:3,3'-dipropylthiacarbocyanine; D002232:Carbocyanines; D003459:Crystallins; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine