Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis
Sarrabeth Stone, Yuan Yue, Milos Stanojlovic, Shuangchan Wu, Gerard Karsenty, Wensheng Lin
Sarrabeth Stone, Yuan Yue, Milos Stanojlovic, Shuangchan Wu, Gerard Karsenty, Wensheng Lin
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Research Article Neuroscience

Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis

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 3

Neuron-specific PERK inactivation did not affect EAE initiation but impaired EAE resolution.

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Neuron-specific PERK inactivation did not affect EAE initiation but impa...
(A) PERK-nKO mice with EAE exhibited persistent, severe neurological deficits, without signs of recovery. n = 12 animals. Error bars represent SEM. Statistical analyses were done with a 2-tailed Mann Whitney test, *P < 0.05. (B and C) Western blot analysis shows that the levels of ATF4 and CHOP were significantly increased in the brains of control EAE mice at PID 22 compared with those in naive mice and that the levels of these proteins were significantly lower in the brains of PERK-nKO mice with EAE at PID 22. (D and E) NeuN and p-eIF2α double immunostaining shows that the level of p-eIF2α was markedly increased in neurons in the layer V of the primary motor cortices of control EAE mice at PID 22 compared with that in naive mice. Importantly, the p-eIF2α level in cortical neurons was noticeably reduced in PERK-nKO mice with EAE compared with that in control EAE mice at PID 22. Scale bars: 50 μm. n = 4 animals. Error bars represent SD. Statistical analyses were done with a 1-way ANOVA with a Tukey’s post test, *P < 0.05.