Fine mapping of gene regions regulating neurodegeneration.
BACKGROUND
Damage 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.


RESULTS
In this study, we use two generations (G8 and G10 cohorts) of an advanced intercross line between DA and PVG(av1) 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
The 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.
Swanberg
Maria
M
Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
Harnesk
Karin
K
Ström
Mikael
M
Diez
Margarita
M
Lidman
Olle
O
Piehl
Fredrik
F
D000483:Alleles; D000818:Animals; D002470:Cell Survival; D002874:Chromosome Mapping / Q000379:methods*; D003433:Crosses, Genetic; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology*; D051381:Rats; D013116:Spinal Cord / Q000473:pathology