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Title: A Mutation in the Gene Encoding Mitochondrial Mg2+ Channel MRS2 Results in Demyelination in the Rat}
Article:
Abstract:
The rat demyelination( dmy) mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system( CNS) after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2( MRS2 magnesium homeostasis factor( Saccharomyces cerevisiae)) gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg2+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg2+ homeostasis in CNS mitochondria is essential for the maintenance of myelin.
Introduction:
Myelin is an essential component of the nervous tissue of higher vertebrates. It acts as a natural insulator of axonal segments allowing, at the same time, the maintenance of axonal integrity and the fast conduction of action potentials. It also reduces ionic currents across the axonal membrane and stabilizes the extracellular milieu within rapidly-firing axon bundles. In the central nervous system( CNS), myelin is produced by oligodendrocytes, while in the peripheral nervous system( PNS), this function is achieved by Schwann cells. Myelination is completed within a relatively short period of time during mammalian development and requires a high rate of production and transport of different kinds of molecules, mostly proteins and lipids. In adult life, myelin is constantly remodeled and the maintenance of functional myelin sheaths requires a careful balance of de novo synthesis and turnover. It is quite clear that any event generating an imbalance in the myelination or remyelination process has the greatest chance of inducing dys- or demyelination of either the central or peripheral nervous system. Our knowledge of the myelination process has benefited from careful observations conducted on human patients affected by one of the many defects of myelination or myelin turnover. It has also benefited from researches carried out on animal models, mostly mutant mice and rats, including those that have been induced by transgenesis or genetic engineering in ES cell lines[1],[2]. Some of these models have even allowed therapies to be developed in a preclinical setting[3]. Unfortunately, only a small number of the many genes that are directly or indirectly involved in the myelination process have been identified and only a few of these genes have been functionally annotated, for example, by the characterization of one or more mutant alleles. For this reason, any new mutation occurring spontaneously or after mutagenesis is of potential interest for unraveling the molecular mechanisms involved in myelin assembly. In an earlier paper we reported the discovery and pathology of a rat mutation designated demyelination( symbol dmy), which is characterized by severe and progressive myelin breakdown in the CNS. We mapped the locus responsible for this myelin disorder to rat chromosome( Chr) 17, very close to the prolactin( Prl) locus, in a region homologous to human Chr 6p21. 1-22. 3 and mouse Chr 13[4],[5]. Based on its pathological features, as well as its genetic localization, this demyelination syndrome appeared to be unique, with no homologue so far reported in any other mammalian species, including humans. In this report we demonstrate that the causative gene( Mrs2) encodes a protein that is an essential component of the major electrophoretic Mg2+ influx system in mitochondria[6]. This gene has orthologues in other organisms, including lower eukaryotes and plants[7],[8]. The protein shares many of the properties of bacterial CorA and yeast Alr1 proteins but its specific involvement in the myelination process was not known or even suspected.
Discussion:
Characterization, by positional cloning, of the molecular defect responsible for the demyelinating phenotype observed in adult dmy/dmy rats led us to incriminate a mutation in the Mrs2 gene. No mutant allele before Mrs2dmy, which we report here, has ever been reported at this locus in any mammalian species. Mrs2 encodes an inner membrane Mg2+ channel in mitochondria and belongs to a family with orthologous copies in a wide range of species[10],[12]. Mrs2 was originally identified in yeast, and orthologous copies of this gene have been identified in a variety of organisms, including bacteria( CorA), fungi( Alr1), and plants( AtMrs2). All proteins in the family have the same substrate selectivity: they transport Mg2+, Co2+ and some other divalent cations across the mitochondrial membrane. Even if these proteins exhibit relatively low sequence similarities, they all have a few important domains at the same relative position and can functionally complement each other over a wide range of phylogenetic distances[16],[17]. In mammals, the normal protein MRS2 has two universally conserved transmembrane domains( TMs) and a conserved Gly-Met-Asn( GMN) motif close to the first TM domain that forms part of the pore and is essential for Mg2+ transport[18]( Figure 2D, Figure S5). As we demonstrated, the protein is truncated in dmy/dmy mutant rats, having lost both of its essential domains and accordingly its function of an Mg2+ transmembrane transporter. In other words, Mrs2dmy is a null allele, which is totally consistent with its recessive allelic interaction. An MRS2 is a major transport for Mg2+ uptake into mitochondria, its function would be expected to be important, if not essential, for the maintenance of respiratory complex I and accordingly for cell viability[6],[11]. This assumption was supported by the analysis of MRS2 knock-down, mediated by shRNA in a human HEK-293 cell line, which resulted in a series of physiological changes ranging from transient reduction of Mg2+ uptake to the complete loss of mitochondrial respiratory complex I, with decreased mitochondrial membrane potential and cell death, depending on the duration of knock-down treatment[11]. However, if we consider the phenotype of our mutant rat, which is apparently limited to the myelination process with a rather long lifespan, the role of MRS2 in the maintenance of cell integrity should be reconsidered. Considering the pathological features that appear to be characteristics of the Mrs2dmy allele on the one hand, and MRS2-specific functions, as described above on the other, it is logical to consider that the demyelinating syndrome in mutant rats results from a mitochondrial disease. This assertion is supported by the observation of an elevated rate of lactic acid in the cerebrospinal fluid, reduced ATP in the brain, increased COX activity, and the morphological alteration of mitochondria, which is generally considered a major characteristic of mitochondrial diseases[13]–[15]. An increase in mitochondria is characteristic of cells with reduced respiratory capacity[19]. The association of mitochondrial dysfunction with demyelination( or leukodystrophy) has been already reported in Leigh syndrome and mitochondrial DNA depletion syndrome[20]–[23]. The tissues most frequently affected in these mitochondrial diseases are the cerebrum, peripheral nerves, and skeletal muscles, presumably because cells of these tissues require more energy than any other cells in the body. Unfortunately, the detailed pathophysiological mechanism( s) leading to demyelination in these diseases has not yet been unraveled. We consider that our mutant rat could be an interesting tool for investigating this matter. Mitochondrial dysfunction has also been observed in multiple sclerosis( MS), one of the most common demyelination diseases, but here again many aspects of the pathophysiology require further investigation[24],[25]. This difficulty of linking gene functions with a specific syndrome is not so surprising if we consider that, according to the most recent estimates, there may be as many as 1, 500 nuclear-encoded mitochondrial proteins[26] and that less than half have been identified with experimental support. Clearly, a complete protein inventory of this organelle across tissues would provide a molecular framework to relate mitochondrial biology and pathogenesis[27]. A point concerning Mrs2 gene expression in the CNS that is worth noting after our experiments and observations is that the gene in question is expressed at a higher rate in neurons than in oligodendrocytes( Figure 4, Figure S3). This was rather unexpected if we consider that oligodendrocytes are the cells actually responsible for myelination of the CNS. At this time, it remains unclear whether the demyelination in dmy/dmy rats is triggered cell-autonomously or cell-nonautonomously. Instead, it is likely that demyelination is enhanced by the surrounding cells, such as activated microglia and astroglia. At 6 weeks of age, when dmy/dmy rats began to exhibit ataxia[9], cytokine levels were elevated and microglia were activated( Figure 5), and it is considered that activated microglia cause neuronal damage through the release of potentially cytotoxic molecules, such as proinflammatory cytokines, reactive oxygen intermediates, proteinases, and complement proteins[28]. Oligodendrocytes show greater vulnerability to such molecules[29],[30]. Additionally, Kuwamura and co-workers reported prominent astrogliosis and many ED-1-positive macrophages in myelin-destroyed areas[9]. When considered together, these morphological observations led us to believe that the demyelination observed in dmy/dmy rats is probably enhanced by activated microglia and astroglia. In summary, we identified Mrs2dmy as a loss-of-function mutation of the Mrs2 gene that normally encodes Mg2+ transporter protein of the mitochondrial inner membrane. Our observations also demonstrate that the mechanisms underlying the initial development of myelin( myelination) are different from those that are involved in its maintenance and turnover since, in Mrs2dmy/Mrs2dmy rats, myelin development is normal while its maintenance is defective. Our mutant rats also appear to be an excellent animal model, not only to evaluate the causal relationships between primary mitochondrial dysfunction and subsequent demyelination, but also for the development of therapies making use, for example, of cell transplantation.
The myelin sheath that surrounds the axon of a neuron acts as a biological insulator . Its major function is to increase the speed at which impulses propagate along myelinated fibers in the central nervous system , as well as the peripheral nervous system . Alterations or damage affecting this structure ( demyelination ) result in the disruption of signals between the brain and other parts of the body . In the rat , mutations producing demyelination have been frequently identified and characterized and have contributed to a better understanding of the genetics of myelin development , physiology , and pathology . This paper reports the molecular characterization of a recessive allele responsible for the progressive disruption of myelin that was initially observed in mutant rats , previously named demyelination ( dmy ) . This mutation generates an additional splicing acceptor site in an intron of the mitochondrial Mg2+ transporter gene ( Mrs2 ) , resulting in the insertion of a 83-bp genomic DNA segment into the Mrs2 transcript and complete functional inactivation of the mutant allele . We firstly defined the biological function of MRS2 in mammals and demonstrated the crucial and unexpected role of MRS2 in myelin physiology . Our findings might be helpful in the development of new therapeutic strategies for demyelinating syndromes .