Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for "gain-of-function" ER diseases.
Schwann cell-derived peripheral myelin protein-22 (PMP-22) when mutated or overexpressed causes heritable neuropathies with a previously unexplained "gain-of-function" endoplasmic reticulum (ER) retention phenotype. In wild-type sciatic nerves, PMP-22 associates in a specific, transient (t(1/2 ) approximately equal to 11 min), and oligosaccharide processing-dependent manner with the lectin chaperone calnexin (CNX), but not calreticulin nor BiP. In Trembler-J (Tr-J) sciatic nerves, prolonged association of mutant PMP-22 with CNX is found (t(1/2) > 60 min). In 293A cells overexpressing PMP-22(Tr-J), CNX and PMP-22 colocalize in large intracellular structures identified at the electron microscopy level as myelin-like figures with CNX localization in the structures dependent on PMP-22 glucosylation. Similar intracellular myelin-like figures were also present in Schwann cells of sciatic nerves from homozygous Trembler-J mice with no detectable activation of the stress response pathway as deduced from BiP and CHOP expression. Sequestration of CNX in intracellular myelin-like figures may be relevant to the autosomal dominant Charcot-Marie-Tooth-related neuropathies.
Dickson
K M
KM
Department of Neurology and Neurosurgery, McGill University, 3640 University Street, Montreal, QC, Canada H3A 2B2.
Bergeron
J J M
JJ
Shames
I
I
Colby
J
J
Nguyen
D T
DT
Chevet
E
E
Thomas
D Y
DY
Snipes
G J
GJ
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D037281:Calnexin; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009422:Nervous System Diseases / Q000235:genetics / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000502:physiology*
D002135:Calcium-Binding Proteins; D017931:DNA Primers; D008565:Membrane Proteins; D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat; D011993:Recombinant Fusion Proteins; D037281:Calnexin