Measles viruses (MV) can be isolated from the brains of deceased subacute sclerosing panencephalitis patients only in a cell-associated form. These viruses are often defective in the matrix (M) protein and always seem to have an altered fusion protein cytoplasmic tail. We reconstituted a cell-free, infectious M-less MV (MV-ΔM) from cDNA. In comparison with standard MV, MV-ΔM was considerably more efficient at inducing cell-to-cell fusion but virus titres were reduced~250-fold. In MV-ΔM-induced syncytia the ribonucleocapsids and glycoproteins largely lost co-localization, confirming the role of M protein as the virus assembly organizer. Genetically modified mice were inoculated with MV-ΔM or with another highly fusogenic virus bearing glycoproteins with shortened cytoplasmic tails (MV-Δ tails ). MV-ΔM and MV-Δ tails lost acute pathogenicity but penetrated more deeply into the brain parenchyma than standard MV. We suggest that enhanced cell fusion may also favour the propagation of mutated, assembly-defective MV in human brains.

Schwann cells express low levels of myelin proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of myelin proteins is elevated, and myelin is formed. For peripheral myelin protein 22 (PMP22), the exact amount of protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique myelin protein in that axonal contact promotes its insertion into the Schwann cell membrane and myelin without altering its rapid turnover rate within the cell.

Peripheral myelin protein 22 (PMP22) is an integral membrane protein that is essential for the normal formation and maintenance of peripheral myelin. Duplications, deletions, or mutations in the PMP22 gene account for a set of dominantly inherited peripheral neuropathies. The heterozygous Trembler-J (TrJ) genotype in mice is similar genetically to a Charcot-Marie-Tooth disease type 1A pedigree in humans, whereas the homozygous TrJ condition leads to the most severe form of PMP22-associated neuropathies. To characterize the consequences of the TrJ mutation, we labeled wild-type (wt-) and TrJ-PMP22 in the third loop of the protein with different epitope tags and expressed them separately or together in COS7 cells and primary Schwann cells. Here we show that the transport of the mutant TrJ-PMP22 is interrupted in the intermediate compartment, preventing its insertion into the plasma membrane and affecting the morphology of the endoplasmic reticulum. In addition, TrJ-PMP22 forms a heterodimer with the wt-PMP22. This interaction causes a fraction of the wt-PMP22 to be retained with TrJ-PMP22 in the intermediate compartment of COS7 and Schwann cells. The relative stability of a wt-mutant PMP22 heterodimer as compared with the wt-wt PMP22 homodimer may determine whether a particular mutation is semidominant or dominant. The neuropathy itself appears to result both from decreased trafficking of wt-PMP22 to the plasma membrane and from a toxic gain of function via the accumulation of wt- and TrJ-PMP22 in the intermediate compartment.

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Peripheral myelin protein 22 (PMP22) is a small, hydrophobic glycoprotein, which is most prominently expressed by Schwann cells as a component of compact myelin of the peripheral nervous system (PNS). Recent progress in molecular genetics revealed that mutations affecting the PMP22 gene including duplications, deletions, and point mutations are responsible for the most common forms of hereditary peripheral neuropathies including Charcot‐Marie‐Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), and a subtype of Dejerine‐Sottas Syndrome (DSS). Functionally, PMP22 is involved in correct myelination during development of peripheral nerves, the stability of myelin, and the maintenance of axons. While most of these functions relate to a role of PMP22 as a structural component of myelin, PMP22 has also been proposed as a regulator of Schwann cell proliferation and differentiation. In this review, we will discuss our current knowledge of PMP22 and its related proteins in the normal organism as well as in disease. In particular, we will focus on how the function of PMP22 and its regulation may be relevant to particular disease mechanisms. Microsc. Res. Tech. 41:359–371, 1998. © 1998 Wiley‐Liss, Inc.