Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice

Abstract

Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1Δ/− mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1Δ/− mice develop age-dependent motor abnormalities, and have a shortened life span of 6–7 months. Pathologically, Ercc1Δ/− mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1Δ/− motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-010-0715-9) contains supplementary material, which is available to authorized users.

Spatio-temporal Analysis of Molecular Determinants of Neuronal Degeneration in the Aging Mouse Cerebellum

“…The upregulation of these classes of proteins marks an increased recruitment of astrocytes and/or other glial cells indicating an increase in neuronal damage and inflammation in the cerebellum of KO mice. This is in line with previous studies that have shown that aging and the lack of efficient DNA repair can trigger neurodegenerative and inflammatory processes (23,(25)(26)(27). Other proteins found to be up-regulated are extracellular proteins that are known to interact with or modify the extracellular environment (HTRA1 and Lama2) as well as cell adhesion molecules (PECAM-1 and MCAM).…”

Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair

“…Macroscopically, the brains of Ercc1 ⌬/Ϫ mice are smaller, but proportional to their reduced body size (de Waard et al, 2010). The gross histological organization analyzed in thionine stained sections appeared normal in all brain areas, including hippocampus ( Fig.…”

“…Consistently, ERCC1-deficient cells show increased sensitivity to agents or treatments that damage DNA, and hence it is expected that these animals accumulate DNA damage at a higher rate than control animals (Sijbers et al, 1996;Muñoz et al, 2005;Ahmad et al, 2008;Hoeijmakers, 2009). Recently it was shown that these animals have age-related neuronal changes in the spinal cord as well as in neuromuscular junctions of the skeletal muscle (de Waard et al, 2010). Here we show that global Ercc1 mutants as well as neuron-specific Ercc1 mutants exhibit an age-dependent decrease in neuronal plasticity, and progressive neuronal pathology, suggestive of neurodegenerative processes.…”

“…The age of 4 months was chosen since at this age animals display clear signs of premature aging, without significant mortality. The maximum lifespan of these mice in the genetically homogeneous F1 C57BL/6J-FVB/N hybrid genetic background used here is ϳ6 months (de Waard et al, 2010).…”

“…A DNA repair defect exclusively in excitatory postnatal forebrain neurons causes gradual neuronal degeneration and reactive astrocytosis Although the aforementioned results showed that the global Ercc1 ⌬/Ϫ mutation significantly affects neuronal health and plasticity, it cannot be ruled out that these outcomes are secondary to the reduced fitness of these animals due to liver, kidney, and other pathology (McWhir et al, 1993;Weeda et al, 1997;Selfridge et al, 2001;Lawrence et al, 2008;de Waard et al, 2010). To examine the direct effect of a DNA repair defect in neurons, and to rule out possibly confounding effects of systemic aging pathology, we made use of the Cre-loxP system to generate mutant mice with a neuron-specific ablation of Ercc1.…”