The axon reaction: identifying the genes that make a difference

Numerous CNS diseases of primarily non-inflammatory origin, such as idiopathic neurodegenerative diseases, contain elements of inflammation, with T cell infiltration, MHC class II expression and neuron/axon damage. Gene mapping in human clinical materials have in most cases failed to unravel discrete genes, since most genes instrumental in non-Mendelian forms of these complex diseases are likely to modestly affect risk, be evolutionary conserved in the population and vary between individuals. We here describe the exploration of susceptibility to neurodegeneration and inflammatory glial activation in response to mechanical nerve injury using experimental genetic models. The response to ventral root avulsion, which is a simple and reproducible model of nerve injury-induced neurodegeneration and inflammation, was examined in a panel of inbred rat strains. A whole genome scan subsequently performed in a F2(DAxPVG) intercross identified quantitative trait loci (QTLs) regulating different features of the nerve injury response. Fine mapping in an advanced intercross line revealed polymorphisms in the Mhc2ta gene as being responsible for strain differences in MHC class II expression. Furthermore, a polymorphism in the syntenic human gene, MHC2TA, was associated both with lower expression of MHC class II-associated genes and increased susceptibility to inflammatory diseases. These results provide important insights into the genetic regulation of fundamental physiological responses of the nervous system to damage and demonstrate relevance also for human diseases.