Fine Mapping of Gene Regions Regulating Neurodegeneration

Maria Swanberg¹^,², Karin Harnesk¹^#, Mikael Ström¹^#, Margarita Diez¹, Olle Lidman¹, Fredrik Piehl¹^*

1 Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden, 2 Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden

Abstract

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.

Methodology/Principal Findings

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/Significance

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.

Citation: Swanberg M, Harnesk K, Ström M, Diez M, Lidman O, et al. (2009) Fine Mapping of Gene Regions Regulating Neurodegeneration. PLoS ONE 4(6): e5906. doi:10.1371/journal.pone.0005906

Editor: Rafael Linden, Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Biofísica da UFRJ, Brazil

Received: March 19, 2009; Accepted: May 19, 2009; Published: June 15, 2009

Copyright: © 2009 Swanberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637 and EURATools, LSHG-CT-2005019015, the Swedish Research Council, Wadsworth Foundation, the Swedish Society for Medical Research, the Swedish Brain Foundation, the Nils and Bibbi Jenssens Foundation, the Montel Williams MS Foundation, the GV80 Foundation, the Soderberg Foundation, and the Swedish Association of Persons with Neurological Disabilities. The funders had no role in study design, data collection or analysis, manuscript preparation or decision to publish.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: fredrik.piehl@ki.se

# These authors contributed equally to this work.