TY - JOUR
T1 - Amyotrophic lateral sclerosis is a distal axonopathy
T2 - Evidence in mice and man
AU - Fischer, Lindsey R.
AU - Culver, Deborah G.
AU - Tennant, Philip
AU - Davis, Albert A.
AU - Wang, Minsheng
AU - Castellano-Sanchez, Amilcar
AU - Khan, Jaffar
AU - Polak, Meraida A.
AU - Glass, Jonathan D.
N1 - Funding Information:
This work was supported by NIH grant P01 NS40405(JDG) and by a grant from the Robert Packard Center for ALS Research at Johns Hopkins. We thank Dr. Mark Rich for helpful discussion and Raphael James, Karen Carney, and Dayna McDermott for technical assistance.
PY - 2004/2
Y1 - 2004/2
N2 - The SOD1 mutant mouse is the most widely used model of human amyotrophic lateral sclerosis (ALS). To determine where and when the pathological changes of motor neuron disease begins, we performed a comprehensive spatiotemporal analysis of disease progression in SOD1G93A mice. Quantitative pathological analysis was performed in the same mice at multiple ages at neuromuscular junctions (NMJ), ventral roots, and spinal cord. In addition, a patient with sporadic ALS who died unexpectedly was examined at autopsy. Mice became clinically weak at 80 days and died at 131 ± 5 days. At 47 days, 40% of end-plates were denervated whereas there was no evidence of ventral root or cell body loss. At 80 days, 60% of ventral root axons were lost but there was no loss of motor neurons. Motor neuron loss was well underway by 100 days. Microglial and astrocytic activation around motor neurons was not identified until after the onset of distal axon degeneration. Autopsy of the ALS patient demonstrated denervation and reinnervation changes in muscle but normal appearing motor neurons. We conclude that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.
AB - The SOD1 mutant mouse is the most widely used model of human amyotrophic lateral sclerosis (ALS). To determine where and when the pathological changes of motor neuron disease begins, we performed a comprehensive spatiotemporal analysis of disease progression in SOD1G93A mice. Quantitative pathological analysis was performed in the same mice at multiple ages at neuromuscular junctions (NMJ), ventral roots, and spinal cord. In addition, a patient with sporadic ALS who died unexpectedly was examined at autopsy. Mice became clinically weak at 80 days and died at 131 ± 5 days. At 47 days, 40% of end-plates were denervated whereas there was no evidence of ventral root or cell body loss. At 80 days, 60% of ventral root axons were lost but there was no loss of motor neurons. Motor neuron loss was well underway by 100 days. Microglial and astrocytic activation around motor neurons was not identified until after the onset of distal axon degeneration. Autopsy of the ALS patient demonstrated denervation and reinnervation changes in muscle but normal appearing motor neurons. We conclude that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.
KW - Axonopathy
KW - Denervation
KW - Sclerosis
UR - http://www.scopus.com/inward/record.url?scp=0345742771&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2003.10.004
DO - 10.1016/j.expneurol.2003.10.004
M3 - Article
C2 - 14736504
AN - SCOPUS:0345742771
SN - 0014-4886
VL - 185
SP - 232
EP - 240
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -