Differential aggregation of the Trembler and Trembler J mutants of peripheral myelin protein 22

Abstract

Mutations in the gene encoding the peripheral myelin protein 22 (PMP22), a tetraspan protein in compact peripheral myelin, are one of the causes of inherited demyelinating peripheral neuropathy. Most PMP22 mutations alter the trafficking of the PMP22 protein in Schwann cells, and this different trafficking has been proposed as the underlying mechanism of the disease. To explore this problem further, we compared the aggregation of wild-type Pmp22 with those of the two Pmp22 mutations found in Trembler (Tr) and Trembler J (TrJ) mice. All three Pmp22s can be crosslinked readily as homodimers in transfected cells. Wild-type Pmp22 also forms heterodimers with Tr and TrJ Pmp22, and these heterodimers traffic with their respective mutant Pmp22 homodimers. All three Pmp22s form complexes larger than dimers with Tr Pmp22 especially prone to aggregate into high molecular weight complexes. Despite the differences in aggregation of Tr and TrJ Pmp22, these two mutant Pmp22s sequester the same amount of wild-type Pmp22 in heterodimers and heterooligomers. Thus, the differences in the phenotypes of Tr and TrJ mice may depend more on the ability of the mutant protein to aggregate than on the dominant-negative effect of the mutant Pmp22 on wild-type Pmp22 trafficking.

Modulation of Epithelial Morphology, Monolayer Permeability, and Cell Migration by Growth Arrest Specific 3/Peripheral Myelin Protein 22

“…The reduced TER and increased flux of small dextrans may indicate that the second loop peptide disrupts homotypic interactions of PMP22. Indeed, PMP22 is known to form dimers and larger oligomers in vivo and in vitro (Tobler et al, 1999(Tobler et al, , 2002. As the extracellular domains of PMP22 share no significant homology with the claudins, a potential direct effect on claudins is unlikely.…”

The formation of peripheral myelin protein 22 aggregates is hindered by the enhancement of autophagy and expression of cytoplasmic chaperones

“…Peripheral myelin protein 22 (PMP22) is a hydrophobic, aggregation-prone, membrane protein expressed mainly in myelinating Schwann cells (SCs) (Snipes et al, 1992;Tobler et al, 2002). In non-myelinating and myelinating SCs, the majority (~80%) of the newly-synthesized PMP22 is rapidly degraded by the UPS, presumably due to misfolding (Pareek et al, 1997).…”

Glycan-independent Role of Calnexin in the Intracellular Retention of Charcot-Marie-Tooth 1A Gas3/PMP22 Mutants

“…Moreover, Gas3/PMP22 mutants tend to form cytosolic aggresomes that may be protective (10 -16). However, whether these misfolding mutations result in disease because of the oligomerization-dependent intracellular sequestration of the wild type (wt) form or by affecting the integrity and function of the ER is still debated (12,17,18).…”