G. Jackson Snipes

Rapid Communication: Human Peripheral Myelin Protein-22 Carries the L2/HNK-1 Carbohydrate Adhesion Epitope

Abstract: Molecular genetic studies have established that mutations in the gene encoding the 22‐kDa peripheral myelin protein (PMP‐22) are responsible for hereditary peripheral neuropathies in the trembler mouse and in a subset of humans with Charcot‐Marie‐Tooth disease, type 1a. The function of the PMP‐22 protein remains unknown. Several studies on myelin proteins in the PNS have indicated that the L2/HNK‐1 epitope, which is believed to be both a ligand for cellular adhesion and a target for autoimmune monoclonal IgM neuritis, may be found on heretofore unidentified proteins with a molecular mass of 19–28 kDa. In this report, we provide immunological evidence that at least one of these proteins is PMP‐22.

Progress in the molecular understanding of hereditary peripheral neuropathies reveals new insights into the biology of the peripheral nervous system.

Since the first description of the autosomal dominant inherited peripheral neuropathy Charcot-Marie-Tooth (CMT) disease over a century ago, there has been considerable disagreement, based on morphological abnormalities of both the axons of peripheral nerves and their surrounding Schwann cells, as to whether this disorder is due primarily to an autonomous Schwann cell defect or an autonomous neuronal defect. Recently, the Schwann cell protein peripheral myelin protein 22 (PMP-22) has been implicated in the molecular pathogenesis of hereditary peripheral neuropathies in mice and humans. Reinterpretations of morphological studies of the diseased nerves in light of these findings strongly suggest that Schwann cells have a much more pronounced influence on their ensheathed axons than previously anticipated.

Oral Curcumin Mitigates the Clinical and Neuropathologic Phenotype of the Trembler-J Mouse: A Potential Therapy for Inherited Neuropathy

Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy. We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants. We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role in selected forms of inherited peripheral neuropathies.

Ultrastructural distribution of PMP22 in Charcot-Marie-Tooth disease type 1A

Peripheral Myelin Protein-22 (PMP22) is a membrane glycoprotein which represents up to 5% of total protein in myelin of peripheral nerves. Mutations affecting the PMP22 gene have been linked to the inherited peripheral neuropathies Charcot-Marie-Tooth disease type 1A (CMT1A; duplications and point mutations), Dejerine-Sottas syndrome (DSS; point mutations), and hereditary neuropathy with liability to pressure palsies (HNPP; deletions). In this study, we determined the ultrastructural distribution of PMP22 and other myelin proteins in normal human peripheral nervous system (PNS) nerves and in CMT1 patients with or without the CMT1A duplication on chromosome 17. Our results demonstrate that PMP22, Po protein, and myelin basic protein are present in compact myelin of all patients examined. PMP22 was also present in the plasma membrane of Schwann cells of unmyelinated fibers and onion bulbs. Although the precise biological role of PMP22 remains to be discovered, our results support the hypothesis that this protein serves multiple functions in Schwann cells

Molecular Basis of Common Hereditary Motor and Sensory Neuropathies in Humans and in Mouse Models

The Hereditary Motor and Sensory Neuropathies (HMSNs) are well known to be clinically, morphologically, and genetically heterogeneous. Yet, recent advances in the cellular and molecular biology of the peripheral nervous system coupled with remarkable progress in human and mouse genetics have provided a framework that has profoundly changed our understanding of the pathogenesis of these diseases. It now appears that most of the HMSNs are related to mutations affecting genes encoding Schwann cell proteins, specifically the Peripheral Myelin Protein PMP22, Myelin Protein Zero, and one of the gap junction proteins, connexin‐32. Accordingly, these findings are discussed in the context of the clinical and pathologic features of the human HMSNs, but are interpreted in the context of basic research findings on the cellular and molecular biology of the peripheral nervous system derived from in vivo and in vitro studies in spontaneously‐occurring and genetically engineered animal models for the HMSNs.

The genetics of myelin

Myelin formation and maintenance requires complex interactions between neurons and glia, and between the integral protein and lipid components of the myelin sheath. Many of the underlying mechanisms may be examined by studying the perturbations caused by spontaneous and targeted mutations in myelin protein genes. This review summarizes the progress in our understanding of these mutations with an emphasis on integrating the recent advances in the genetics of myelin into a more generalized view of myelin organization and function.

Pleomorphic granular cell astrocytoma of the pineal gland.

Background. Primary neoplasms of the pineal gland are uncommon. Two patients with unusual primary pineal tumors that had similar distinctive histologic features are reported.

Curcumin facilitates a transitory cellular stress response in Trembler-J mice

We have previously shown that oral administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and partially mitigates the severe neuropathy phenotype of the Trembler-J (Tr-J) mouse model in a dose-dependent manner. Here we compared the gene expression in sciatic nerves of 2-week-old pups and adult Tr-J with the same age groups of wild-type mice and found a significant increase in gene expression for hypoxia, inflammatory response and heat-shock proteins, the latter specifically the Hsp70 family, in Tr-J mice. We also detected an activation of different branches of unfolded protein responses (UPRs) in Tr-J mice. Administering curcumin results in lower expression of UPR markers suggesting it relieves endoplasmic reticulum (ER) cell stress sensors in sciatic nerves of Tr-J mice while the level of heat-shock proteins stays comparable to untreated Tr-J mice. We further tested if Hsp70 levels could influence the severity of the Tr-J neuropathy. Notably, reduced dosage of the Hsp70 strongly potentiates the severity of the Tr-J neuropathy, though the absence of Hsp70 had little effect in wild-type mice. In aggregate, these data provide further insights into the pathological disease mechanisms caused by myelin gene mutations and further support the exploration of curcumin as a therapeutic approach for selected forms of inherited neuropathy and potentially for other genetic diseases due to ER-retained mutants.

Chapter 32 The molecular basis of the neuropathies of mouse and human

Publisher Summary This chapter discusses the discovery of a gene for peripheral myelin protein 22 (PMP22) and its involvement in trembler neurological mutants. The cDNA for PMP22 was found in three independent library screens, two comparing the cDNAs from libraries made from normal rat sciatic nerve and from sciatic nerve after injury and the other comparing the cDNAs of quiescent and proliferating fibroblasts. In the latter instance, the gene was referred to as the growth arrest specific gene-3 because of its potential involvement in controlling growth in these cells. The cDNA encodes a small, extremely hydrophobic protein of 160 amino acid residues, with four putative membrane spanning domains and one asparagine-linked glycosylation site. Expression of PMP22 correlates with myelin formation and myelin-specific gene expression during sciatic nerve development and its down-regulation after nerve injury follows that of the myelin protein Po. In situ hybridization confirmed that PMP22 mRNA is synthesized by Schwann cells. PMP22 mRNA expression is clearly regulated by axon contact and is found mainly in the peripheral nervous system (PNS). The chapter discusses PMP22 and the inherited peripheral neuropathies in human, along with human peripheral neuropathies associated with mutations in other PNS myelin genes.