Abstract
Myelinating Schwann cells specifically express L-periaxin (L-PRX) in the mammalian peripheral nervous system. Several loss-of-function mutations in periaxin have been described and linked to autosomal recessive Dejerine Sottas neuropathy and to demyelinating Charcot-Marie-Tooth disease. The localization of L-periaxin is developmentally regulated in the nucleus and the plasma membrane of Schwann cells. In this study, L-periaxin, which contains a PDZ domain, a nuclear localization signal (NLS) domain, a repeat domain, and an acidic domain, was localized in the cytoplasm of RSC96 cells. By contrast, a mutant L-periaxin with a deleted PDZ domain was localized mainly in the nucleus of RSC96 cells. After a nuclear cyclin A1, which is localized exclusively in the nucleus, was fused with the PDZ domain, cyclinA1was found in the cytoplasm of RSC96 cells. Treatment with leptomycin B (LMB), a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signal (NES), also causes nuclear accumulation of wild-type L-periaxin. Double leucine mutation (L83, 85Q) in the putative NES in the PDZ domain prevented L-periaxin nuclear export and induced nuclear accumulation. These results suggested that the localization of L-periaxin in the cytoplasm is supported by NES in the PDZ domain.
Highlights
Periaxin is a non-compact myelin protein in the peripheral nervous system (PNS) [1]
The RSC96 cells transfected with these plasmids were subjected to fluorescence analysis and revealed that L-PRX was predominantly localized in the cytoplasm (Fig. 1B)
The results indicated that Leptomycin B (LMB) treatment reduced the distribution of enhanced green fluorescent protein (EGFP)-L-periaxin and EGFP-PDZ-cyclin A1 in the cytoplasm (Fig.3B and 3C)
Summary
Periaxin is a non-compact myelin protein in the peripheral nervous system (PNS) [1]. Periaxin gene has been characterized in Dejerine-Sottas [2] and Type 4F Charcot-Marie-Tooth degenerating peripheral neuropathies [3,4]. Similar to other proteins that contain a PDZ domain, L-periaxin is localized in the plasma membrane of myelinating Schwann cells. L-periaxin stabilizes the dystroglycan glycoprotein complex (DGC) by directly interacting with dystrophin-related protein 2 (DRP2) in a macromolecular complex that may provide a link between the extracellular matrix and the Schwann cell [9,10]. Quantitative studies have shown that periaxin comprises 16% by weight of PNS myelin protein, whereas DRP2 contains 0.2% [12]. These values are inconsistent with an exclusive stoichiometric relationship between periaxin and Drp in a dystroglycan complex, suggesting that periaxin has other functions in addition to PDG complex formation and appositions [11]. L-periaxin forms homodimers via a PDZ domain and clusters PDG complexes in the Schwann cell plasma membrane.In DPDZ-PRX mice, it reduced Schwann cell elongation and retarded but not prevented development of normal conduction velocities to a maximum value [13]
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