TY - JOUR
T1 - Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice
AU - Jeong, Suh Young
AU - Crooks, Daniel R.
AU - Wilson-Ollivierre, Hayden
AU - Ghosh, Manik C.
AU - Sougrat, Rachid
AU - Lee, Jaekwon
AU - Cooperman, Sharon
AU - Mitchell, James B.
AU - Beaumont, Carole
AU - Rouault, Tracey A.
N1 - KAUST Repository Item: Exported on 2020-10-01
PY - 2011/10/7
Y1 - 2011/10/7
N2 - Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.
AB - Genetic ablation of Iron Regulatory Protein 2 (Irp2, Ireb2), which post-transcriptionally regulates iron metabolism genes, causes a gait disorder in mice that progresses to hind-limb paralysis. Here we have demonstrated that misregulation of iron metabolism from loss of Irp2 causes lower motor neuronal degeneration with significant spinal cord axonopathy. Mitochondria in the lumbar spinal cord showed significantly decreased Complex I and II activities, and abnormal morphology. Lower motor neurons appeared to be the most adversely affected neurons, and we show that functional iron starvation due to misregulation of iron import and storage proteins, including transferrin receptor 1 and ferritin, may have a causal role in disease. We demonstrated that two therapeutic approaches were beneficial for motor neuron survival. First, we activated a homologous protein, IRP1, by oral Tempol treatment and found that axons were partially spared from degeneration. Secondly, we genetically decreased expression of the iron storage protein, ferritin, to diminish functional iron starvation. These data suggest that functional iron deficiency may constitute a previously unrecognized molecular basis for degeneration of motor neurons in mice.
UR - http://hdl.handle.net/10754/325294
UR - https://dx.plos.org/10.1371/journal.pone.0025404
UR - http://www.scopus.com/inward/record.url?scp=80053902000&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0025404
DO - 10.1371/journal.pone.0025404
M3 - Article
C2 - 22003390
SN - 1932-6203
VL - 6
SP - e25404
JO - PLoS ONE
JF - PLoS ONE
IS - 10
ER -