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Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis
Sarrabeth Stone, … , Gerard Karsenty, Wensheng Lin
Sarrabeth Stone, … , Gerard Karsenty, Wensheng Lin
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(2):e124232. https://doi.org/10.1172/jci.insight.124232.
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Categories: Research Article Neuroscience

Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis

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Abstract

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating and neurodegenerative diseases of the CNS. Although neurodegeneration is the major contributor to chronic disability in MS, mechanisms governing the viability of axons and neurons in MS and EAE remain elusive. Data indicate that activation of pancreatic endoplasmic reticulum kinase (PERK) influences, positively or negatively, neuron and axon viability in various neurodegenerative diseases through induction of ATF4. In this study, we demonstrate that the PERK pathway was activated in neurons during EAE. We found that neuron-specific PERK inactivation impaired EAE resolution and exacerbated EAE-induced axon degeneration, neuron loss, and demyelination. Surprisingly, neuron-specific ATF4 inactivation did not alter EAE disease course or EAE-induced axon degeneration, neuron loss, and demyelination. These results suggest that PERK activation in neurons protects axons and neurons against inflammation in MS and EAE through ATF4-independent mechanisms.

Authors

Sarrabeth Stone, Yuan Yue, Milos Stanojlovic, Shuangchan Wu, Gerard Karsenty, Wensheng Lin

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Figure 10

Neuron-specific ATF4 did not affect axon loss, demyelination, or neuron loss during EAE.

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Neuron-specific ATF4 did not affect axon loss, demyelination, or neuron ...
(A–C) SMI31 IHC shows that neuron-specific ATF4 inactivation did not change the number of axons in the lumbar spinal cords of EAE mice at PID 60. (D–F) MBP IHC shows that neuron-specific ATF4 inactivation did not change the extent of demyelination in the lumbar spinal cords of EAE mice at PID 60. (G–I) NeuN IHC shows that neuron-specific ATF4 inactivation did not significantly change the number of neurons in the layer V of the primary motor cortex at PID 60. Scale bars: 50 μm (A, B, G, and H); 100 μm (D and F). n = 4 animals. Error bars represent SD. Statistical analyses were done with a 2-tailed t test.
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Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

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