TY - JOUR
T1 - Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria
AU - Liu, Jian
AU - Lillo, Concepción
AU - Jonsson, P. Andreas
AU - Velde, Christine Vande
AU - Ward, Christopher M.
AU - Miller, Timothy M.
AU - Subramaniam, Jamuna R.
AU - Rothstein, Jeffery D.
AU - Marklund, Stefan
AU - Andersen, Peter M.
AU - Brännström, Thomas
AU - Gredal, Ole
AU - Wong, Philip C.
AU - Williams, David S.
AU - Cleveland, Don W.
N1 - Funding Information:
We would like to thank David R. Borchelt (Johns Hopkins University) and Pico Caroni (Novartis Research Foundation, Basel, Switzerland) for generously providing us with spinal cord materials from SOD1 H46R/H48Q and Thy1-SOD1 G85R transgenic mice, respectively. We would also like to thank Karen Teofilo for quantification analysis of the Immuno-EM study. This work has been supported by grants from the NIH (NS27036 to D.W.C., NS40014 to P.C.W., and EY07042 and EY12598 to D.S.W.), from the Spinal Cord Foundation to J.L., and from the Bjorklund Foundation for ALS Research to P.M.A. J.L. and C.V.V. have been supported by postdoctoral fellowships from the Paralyzed Veterans of America Spinal Cord Research Foundation; T.M.M. was supported by a Physician/Scientist award from the NIH (AG 000975). D.W.C. receives salary support from the Ludwig Institute for Cancer Research.
PY - 2004/7/8
Y1 - 2004/7/8
N2 - One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.
AB - One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.
UR - http://www.scopus.com/inward/record.url?scp=3242701496&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2004.06.016
DO - 10.1016/j.neuron.2004.06.016
M3 - Article
C2 - 15233913
AN - SCOPUS:3242701496
SN - 0896-6273
VL - 43
SP - 5
EP - 17
JO - Neuron
JF - Neuron
IS - 1
ER -