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 3

Deletion of BAX/BAK preserves neuronal function.

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Deletion of BAX/BAK preserves neuronal function. (A and C) Control, symp...
(A and C) Control, symptomatic, and end-stage are as defined as in the legend for Figure 2. (A) Representative ventral root sections from control and SOD1G93A mice stained with toluidine blue. Scale bar: 200 μm. (B) Quantitation of myelinated ventral root axons from control and SOD1G93A mice. n = 3. (C) Representative neuromuscular junction images from control and SOD1G93A mice stained with FITC-conjugated α-bungarotoxin (green) and antibody to Tuj1 (red). Asterisks and arrowheads indicate fully innervated and partially innervated neuromuscular junctions, respectively. Notice the rounded, degenerated appearance of the SOD1G93ACreCNS symptomatic neuromuscular junction. nAchR, nicotinic acetylcholine receptor. Scale bar: 8 μm. (D) Percentage of innervated synapses in control and SOD1G93A mice as quantified from neuromuscular junction staining. n = 2. (E) Percentage of the longest rotarod performance by each mouse (n = 3 for each group). P < 0.05 via ANOVA. (B and E) Data were analyzed using unpaired 2-tailed Student’s t test. ψ indicates that all mice were deceased at the indicated time point.