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

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Abstract

A large number of molecular pathways have been implicated in the degeneration of axotomized motoneurons. We previously have demonstrated substantial differences in the survival rate of axotomized motoneurons across different rat strains. Identification of genetic differences underlying such naturally occurring strain differences is a powerful approach, also known as forward genetics, to gain knowledge of mechanisms relevant for complex diseases, like injury-induced neurodegeneration. Overlapping congenic rat strains were used to fine map a gene region on rat chromosome eight previously shown to regulate motoneuron survival after ventral root avulsion. The smallest genetic fragment, R5, contains 35 genes and displays a highly significant regulatory effect on motoneuron survival. Furthermore, expression profiling in a F2(DAxPVG) intercross demonstrates one single cis-regulated gene within the R5 fragment; Gsta4, encoding glutathione S-transferase alpha-4. Confirmation with real-time PCR shows higher Gsta4 expression in PVG compared with DA both in naïve animals and at several time points after injury. Immunolabeling with a custom made rat Gsta4 antibody demonstrates a neuronal staining pattern, with a strong cytoplasmic labeling of motoneurons. These results demonstrate and map naturally occurring genetic differences in the expression of Gsta4 is associated both with a highly significant increase in the survival of axotomized motoneurons and with a trans-regulation of several molecular pathways involved in neurodegenerative processes. This adds to a large body of evidence implicating lipid peroxidation as an important pathway for neurodegeneration.

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Abbreviations

4-HNE:

4-Hydroxynonenal

AD:

Alzheimer’s disease

AIL:

Advanced intercross line

ALS:

Amyotrophic lateral sclerosis

BSA:

Bovine serum albumin

CNS:

Central nervous system

DA:

Dark Agouti

eQTL:

Expression QTL

Gsta4:

Glutathione S-transferase alpha4

MS:

Multiple sclerosis

NeuN:

Neuronal nuclei

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

PVG:

Piebald Virol Glaxo

ROS:

Reactive oxygen species

SOD1:

Superoxide dismutase 1

QTL:

Quantitative trait locus

VRA:

Ventral root avulsion

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Acknowledgments

We thank Prof. Tomas Olsson for expert advice. Further, Matthias Heinig and Norbert Hübner at MDC, Berlin, for help with the eQTL data analysis and Peter Lundbäck at the Rheumatology unit, Karolinska Institutet, CMM, for help and expertise in Western Blot. This study was supported by the 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637, EURATools, LSHG-CT-2005019015, and the 7th Framework Program of the European Union, EURATrans, HEALTH-F4-2010-241504, by the Swedish Research Council, the Swedish Brain Foundation and the Swedish Association of Persons with Neurological Disabilities. Centre for Stochastic Geometry and advanced Bioimaging was supported by the Villum Foundation. The funders had no role in study design, data collection or analysis, manuscript preparation or decision to publish.

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No competing interests are declared.

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Authors and Affiliations

  1. Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, 17176, Stockholm, Sweden

    Mikael Ström, Faiez Al Nimer, Rickard Lindblom & Fredrik Piehl

  2. Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark

    Jens Randel Nyengaard

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  1. Mikael Ström
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  2. Faiez Al Nimer
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Correspondence to Mikael Ström.

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Faiez Al Nimer and Rickard Lindblom contributed equally to the work.

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Ström, M., Al Nimer, F., Lindblom, R. et al. Naturally Occurring Genetic Variability in Expression of Gsta4 is Associated with Differential Survival of Axotomized Rat Motoneurons. Neuromol Med 14, 15–29 (2012). https://doi.org/10.1007/s12017-011-8164-8

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