TY - JOUR
T1 - Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice
AU - De Waard, Monique C.
AU - Van Der Pluijm, Ingrid
AU - Zuiderveen Borgesius, Nils
AU - Comley, Laura H.
AU - Haasdijk, Elize D.
AU - Rijksen, Yvonne
AU - Ridwan, Yanto
AU - Zondag, Gerben
AU - Hoeijmakers, Jan H.J.
AU - Elgersma, Ype
AU - Gillingwater, Thomas H.
AU - Jaarsma, Dick
N1 - Funding Information:
Acknowledgments We thank Sofie van Tuijl for her assistance. This work was supported by the Prinses Beatrix Fonds (DJ), the Netherlands Organization for Scientific Research (ZonMW-TOP; YE), BBSRC (THG/LHC), BDFNewlife (THG) and the Wellcome Trust (THG).
PY - 2010/10
Y1 - 2010/10
N2 - 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 Ercc1 Δ/- mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1 Δ/- mice develop age-dependent motor abnormalities, and have a shortened life span of 6-7 months. Pathologically, Ercc1 Δ/- 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, Ercc1 Δ/- 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.
AB - 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 Ercc1 Δ/- mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1 Δ/- mice develop age-dependent motor abnormalities, and have a shortened life span of 6-7 months. Pathologically, Ercc1 Δ/- 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, Ercc1 Δ/- 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.
UR - http://www.scopus.com/inward/record.url?scp=77956189163&partnerID=8YFLogxK
U2 - 10.1007/s00401-010-0715-9
DO - 10.1007/s00401-010-0715-9
M3 - Article
C2 - 20602234
AN - SCOPUS:77956189163
SN - 0001-6322
VL - 120
SP - 461
EP - 475
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -