Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis
Nichole A. Reyes, … , Eric J. Huang, Scott A. Oakes
Nichole A. Reyes, … , Eric J. Huang, Scott A. Oakes
Published September 20, 2010
Citation Information: J Clin Invest. 2010;120(10):3673-3679. https://doi.org/10.1172/JCI42986.
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Research Article Neuroscience

Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis

Abstract

Apoptosis of motor neurons is a well-documented feature in amyotrophic lateral sclerosis (ALS) and related motor neuron diseases (MNDs). However, the role of apoptosis in the pathogenesis of these diseases remains unresolved. One possibility is that the affected motor neurons only succumb to apoptosis once they have exhausted functional capacity. If true, blocking apoptosis should confer no therapeutic benefit. To directly investigate this idea, we tested whether tissue-specific deletion in the mouse CNS of BCL2-associated X protein (BAX) and BCL2-homologous antagonist/killer (BAK), 2 proapoptotic BCL-2 family proteins that together represent an essential gateway to the mitochondrial apoptotic pathway, would protect against motor neuron degeneration. We found that neuronal deletion of Bax and Bak in a mouse model of familial ALS not only halted neuronal loss, but prevented axonal degeneration, symptom onset, weight loss, and paralysis and extended survival. These results show that motor neurons damaged in ALS activate the mitochondrial apoptotic pathway early in the disease process and that apoptotic signaling directly contributes to neuromuscular degeneration and neuronal dysfunction. Hence, inhibiting apoptosis upstream of mitochondrial permeabilization represents a possible therapeutic strategy for preserving functional motor neurons in ALS and other MNDs.

Authors

Nichole A. Reyes, Jill K. Fisher, Kathryn Austgen, Scott VandenBerg, Eric J. Huang, Scott A. Oakes

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Figure 2

SOD1G93ADKOCNS neurons lack morphological features of apoptosis but show evidence of autophagy.

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SOD1G93ADKOCNS neurons lack morphological features of apoptosis but sho...
(A–D) Transmission electron microscope images of motor neurons from control and SOD1G93A mice. (A and E) Control mice were harvested at 120 days. Symptom onset [symptomatic] began at 90 days and 120 days for SOD1G93ACreCNS and SOD1G93ADKOCNS mice, respectively. End-stage began at 120 days and 150 days for SOD1G93ACreCNS and SOD1G93ADKOCNS mice, respectively. (B–D) The SOD1G93ADKOCNS animal was harvested at end-stage (156 days). (A) Motor neurons from SOD1G93ACreCNS animals appear apoptotic, while motor neurons from SOD1G93ADKOCNS animals appear healthy. Scale bars: 5 μm. (B) SOD1G93ADKOCNS motor neurons display morphological features of autophagy. Scale bar: 0.5 μm. (C) SOD1G93ADKOCNS motor axons are dystrophic and contain lysosomes. Scale bar: 5 μm. (D) Increased intracellular aggregates in SOD1G93ADKOCNS motor neurons. Scale bar: 2 μm. (E) Representative LC3 (brown) and p62 (green) staining of the anterior horn region of spinal cords from control and SOD1G93A mice. Arrows indicate motor neurons (top row) and positive p62 staining (bottom row). Scale bar: 100 μm (top row); 50 μm (bottom row). A, aggregates; AV, autophagic vesicle; L, lysosome; M, mitochondria; N, nucleus.