Expression of Golli proteins in adult human brain and multiple sclerosis lesions
Introduction
Multiple sclerosis (MS) is an inflammatory disease of autoimmune origin, with massive demyelination, oligodendrocyte death and axonal degeneration Raine, 1994, Raine, 1997, Steinman, 1996, Ferguson et al., 1997, Prineas and McDonald, 1997, Trapp et al., 1999. Myelin basic proteins (MBPs) are the major constituent proteins of myelin, which is damaged in MS. In both rodent and human, the MBP gene is a part of a larger gene complex called Golli-MBP (Campagnoni et al., 1993). Human Golli-MBP complex is a locus of 179 kb containing at least 11 exons and giving rise to two families of structurally related proteins, Golli (gene expressed in the oligodendrocyte lineage) and MBPs, from two different transcriptional start sites Campagnoni et al., 1993, Pribyl et al., 1993, Landry et al., 1998. Two human Golli mRNAs (HOG7 and HOG5), that overlap with classic MBP transcripts, have been characterized. They give rise to two Golli proteins that contain 133-amino acid sequence unique for Golli, but also some classic MBP epitopes (Campagnoni et al., 1993). During development, Golli-MBP proteins and transcripts are expressed in wide variety of cells belonging both to the immune (thymus, lymph nodes, spleen) and nervous system (neurons, oligodendrocytes, microglia) Zelenika et al., 1993, Mathisen et al., 1993, Grima et al., 1994, Pribyl et al., 1996a, Pribyl et al., 1996b, Landry et al., 1997, Landry et al., 1998, Zecevic et al., 1998, Givogri et al., 2001, Tosic et al., 2002. In addition, Golli-MBP mRNAs and proteins were described in adult mouse thymocytes and macrophages Fritz and Kalvakolanu, 1995, Fritz and Zhao, 1996. Although it was believed that “classic” MBPs are expressed only in myelin-producing cells—Schwann cells and oligodendrocytes—recent findings showed their expression in lymph nodes, spleen and thymus Fritz and Zhao, 1996, Mor et al., 1998, Liu et al., 2001. Results from several laboratories indicate that the Golli part of Golli-MBP proteins can play a role in autoimmune processes as an additional autoimmunogen Tranquill et al., 1996, Fritz and Zhao, 1996, MacKenzie-Graham et al., 1997, Clark et al., 1999, Givogri et al., 2000, Feng et al., 2000.
Golli proteins so far have not been investigated either in the normal human adult CNS or in MS patients. In this study, our goal was first to resolve whether Golli-MBP gene was transcribed and translated into protein in the adult human CNS. Second, we wanted to determine whether the expression of Golli proteins and mRNAs were up-regulated in brain tissue from MS patients. Double-labeling experiments with cell-specific markers and antibodies were done in combination with Golli antibody to specify cell types that expressed Golli proteins. In addition, antibody to heterogeneous nuclear ribonucleoprotein (hnRNP) A2 implicated in RNA processing and trafficking Dreyfuss et al., 1993, Hoek et al., 1998, was used to determine whether the transport of MBP was changed in MS.
Since our results showed the increased number of oligodendrocyte progenitors around the chronic MS lesion, we investigated the expression of chemokine, growth-regulated oncogene alpha (GROα). This chemokine was reported to promote spinal cord oligodendrocyte precursor proliferation in vitro (Robinson et al., 1998). It also has been reported to be up-regulated in experimental autoimmune encephalitis (EAE), an animal model of MS (Glabinski et al., 1997).
Section snippets
Tissue
Tissue from MS patients was mainly obtained from the collection of Dr. Cedric Raine (Albert Einstein University, Bronx, NY). Additional tissue came from the brain banks of the University of Maryland and the University of California, Los Angeles. The ages of patients at the time of death ranged from 27 to 86 years, and average duration of illness of chronic cases was 15 years (n=12, Table 1). The control cases (n=4), with the age ranging from 49 to 70 years, died from diseases not affecting the
Results
The expression of Golli proteins was studied in three areas within the white matter of the telencephalon: the lesion, the border of the lesion and unaffected white matter in chronic (n=12) and one acute case of MS. These results were compared to white matter of age-matched control human brains (n=4).
A single acute MS case available for this study was insufficient to draw any conclusions, but it is presented as an indication of possible different regulation of Golli expression in two clinical
Discussion
Present results demonstrate that Golli proteins are expressed in the adult CNS, and that their expression is up-regulated in chronic MS cases. Golli proteins are expressed in oligodendrocyte precursor cells (OPCs), microglia/macrophages, and axons, in and around lesions of chronic and acute MS. Simultaneous presence of Golli proteins in the cells of the immune and nervous system could explain their autoimmunogen properties.
Acknowledgments
We are grateful to Dr. Cedric Raine for letting us share his tissue collection and for helpful discussion; to Dr. Barbarese for useful comments on early version of this manuscript, as well as Drs. Campagnoni, Bansal, Levine and Rigby for gift of antibodies, and Dr. Tosic for gift of human 5a and 5c clones.
Some tissue specimens were obtained from the National Neurological Research Specimen Bank, VAMC, Los Angeles, CA 90073, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society,
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Present address: Department of Anatomy and Developmental Biology, University College London, London, UK.