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Aggregation of peripheral myelin protein 22 in Trembler J neuropathy nerves
Author(s) -
Notterpek L.,
Fortun J.,
Ferguson T. A.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.45_3.x
Subject(s) - peripheral myelin protein 22 , myelin , microbiology and biotechnology , ubiquitin , protein aggregation , biology , proteostasis , immunoprecipitation , chemistry , biochemistry , neuroscience , gene , central nervous system
Mutations in the peripheral myelin protein 22 (PMP22) gene are associated with demyelinating neuropathies leading to muscle atrophy. Altered subcellular trafficking and aggregation of mutant PMP22s have been proposed as mechanisms for the neuropathy. Indeed, wild type PMP22 accumulates in aggresomes when the ubiquitin‐proteasome pathway is inhibited or PMP22 is overexpressed. Therefore, we investigated the presence of PMP22 aggregates in sciatic nerves of adult heterozygote Trembler J (TrJ) mice. Our studies show the accumulation of PMP22 in perinuclear, as well as peripheral aggregates in affected samples. PMP22 aggregates are surrounded by a vimentin cage and often colocalize with ubiquitin. Other myelin proteins, including myelin basic protein, are diverted to PMP22 aggregates in TrJ nerves. In addition, connexin 32 and protein 0 aggregates are detected in affected Schwann cells. Biochemical analyses of nerve lysates confirm the up‐regulation of the ubiquitin‐proteasomal and lysosomal protein degradation pathways. In addition, missfolding of the mutant TrJ PMP22 induces a stress response in the Schwann cells, as revealed by the elevated levels of molecules involved in protein folding, such as Hsp60, Hsp70 and alpha β crystalline. Our results support a possible mechanism by which the L16P mutation in PMP22 increases the tendency of the protein to aggregate and sequester other proteins, such as chaperones and myelin proteins, interfering with normal processes in Schwann cells. Acknowledgements: These studies are supported by funds from the NIH and the Muscular Dystrophy Association.