Fine Mapping of Gene Regions Regulating Neurodegeneration

Abstract

BackgroundDamage to nerve cells and axons leading to neurodegeneration is a characteristic feature of many neurological diseases. The degree of genetic influence on susceptibility to axotomy-induced neuronal death has so far been unknown. We have examined two gene regions, Vra1 and Vra2, previously linked to nerve cell loss after ventral root avulsion in a rat F2 intercross between the DA and PVG inbred rat strains.Methodology/Principal FindingsIn this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVGav1 to reproduce linkage to Vra1 and to fine-map this region. By isolating the effect from Vra1 in congenic strains, we demonstrate that Vra1 significantly regulates the loss of motoneurons after avulsion. The regulatory effect mediated by Vra1 thus resides in a congenic fragment of 9 megabases. Furthermore, we have used the advanced intercross lines to give more support to Vra2, originally detected as a suggestive QTL.Conclusions/SignificanceThe results demonstrated here show that naturally occurring allelic variations affect susceptibility to axotomy-induced nerve cell death. Vra1 and Vra2 represent the first quantitative trait loci regulating this phenotype that are characterized and fine mapped in an advanced intercross line. In addition, congenic strains provide experimental evidence for the Vra1 effect on the extent of injury-induced neurodegeneration. Identification of the underlying genetic variations will increase our understanding of the regulation and mechanisms of neurodegeneration.

Astrocytic Expression of GSTA4 Is Associated to Dopaminergic Neuroprotection in a Rat 6-OHDA Model of Parkinson’s Disease

“…No QTL thus far has been identified in rat PD models, but susceptibility to neurodegeneration has been studied in rats after the nerve injury VRA [ 9 ]. The QTL Vra1 on rat chromosome 8 was identified as being linked to neuroprotection after VRA [ 9 ] and also shown to confer protection to TBI [ 11 ].…”

“…Rats carrying PVG.1AV1 alleles in the Vra1 region were back-crossed multiple times to DA to create the DA.VRA1 congenic strain, carrying PVG.1AV1 alleles in the neuroprotective Vra1 region on a DA strain background. This strain was used to finely map Vra1 , and several candidate genes were discovered [ 9 ]. A later study determined Glutathione S -transferase alpha 4 ( Gsta4 ) as the strongest candidate gene regulating neurodegeneration in response to VRA [ 10 ] and traumatic brain injury (TBI) in DA.VRA1 congenic rats [ 11 ].…”

Naturally Occurring Genetic Variability in Expression of Gsta4 is Associated with Differential Survival of Axotomized Rat Motoneurons

“…A subsequent study in a DA x PVG intercross pinpointed a locus at chromosome 8 (VRA1) to regulate neurodegeneration (Lidman et al 2003). Following from this finding, a genetic fragment that corresponds to the Vra1 locus was introgressed from the PVGA strain into DA background to produce a congenic strain (DA.PVG av1 -Vra1-R3) that was indeed shown to display higher motorneuron survival compared to the PVGA strain (Swanberg et al 2009). In paper III, a congenic that narrowed down the introgressed PVG fragment to 35 genes (DA.PVG av1 -Vra1-R5), still displayed better motorneuron survival than the parental DA.…”

Naturally Occurring Variation in the Glutathione-S-Transferase 4 Gene Determines Neurodegeneration After Traumatic Brain Injury

“…Indeed, when 4-HNE is injected directly into the brain, apoptotic nerve cells are present at one day after the injection both in the area of the injection but also in the hippocampus. We have previously performed an unbiased complex trait mapping of motor neuron loss after ventral root avulsion in the DA and PVG av1 strains, where a significant linkage was identified on chromosome 8 (19,43). Also a whole genome expression QTL mapping in a F2(DAxPVG av1 ) intercross combined with fine mapping using congenic strains in the ventral root avulsion model identified one single transcript being highly strain regulated; Gsta4 (42).…”

“…The DA.PVG av1 -Vra1R5 (RNO8: D8Rat24-D8Got132 [82.2-88.6 Mb]) (hereafter called R5) congenic was bred in-house as described previously (43). The genome of the R5 congenic has all genes from the DA strain except 35 genes, including Gsta4, from the PVG av1 strain.…”