Coin-sized, fully integrated, and minimally invasive continuous glucose monitoring system based on organic electrochemical transistors.

Continuous glucose monitoring systems (CGMs) are critical toward closed-loop diabetes management. The field's progress urges next-generation CGMs with enhanced antinoise ability, reliability, and wearability. Here, we propose a coin-sized, fully integrated, and wearable CGM, achieved by holistically synergizing state-of-the-art interdisciplinary technologies of biosensors, minimally invasive tools, and hydrogels. The proposed CGM consists of three major parts: (i) an emerging biochemical signal amplifier, the organic electrochemical transistor (OECT), improving the signal-to-noise ratio (SNR) beyond traditional electrochemical sensors; (ii) a microneedle array to facilitate subcutaneous glucose sampling with minimized pain; and (iii) a soft hydrogel to stabilize the skin-device interface. Compared to conventional CGMs, the OECT-CGM offers a high antinoise ability, tunable sensitivity and resolution, and comfort wearability, enabling personalized glucose sensing for future precision diabetes health care. Last, we discuss how OECT technology can help push the limit of detection of current wearable electrochemical biosensors, especially when operating in complicated conditions.

The physiological role of the unfolded protein response in the nervous system.

The unfolded protein response (UPR) is a cellular stress response pathway activated when the endoplasmic reticulum, a crucial organelle for protein folding and modification, encounters an accumulation of unfolded or misfolded proteins. The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity, reducing protein biosynthesis, and promoting protein degradation. It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress. Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system. Here, we provide an overview of recent findings that underscore the UPR's involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions, and highlight the critical role of the UPR in brain development, memory storage, retinal cone development, myelination, and maintenance of myelin thickness.

Mechanisms Governing Oligodendrocyte Viability in Multiple Sclerosis and Its Animal Models.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which is triggered by an autoimmune assault targeting oligodendrocytes and myelin. Recent research indicates that the demise of oligodendrocytes due to an autoimmune attack contributes significantly to the pathogenesis of MS and its animal model experimental autoimmune encephalomyelitis (EAE). A key challenge in MS research lies in comprehending the mechanisms governing oligodendrocyte viability and devising therapeutic approaches to enhance oligodendrocyte survival. Here, we provide an overview of recent findings that highlight the contributions of oligodendrocyte death to the development of MS and EAE and summarize the current literature on the mechanisms governing oligodendrocyte viability in these diseases.

The UPR Maintains Proteostasis and the Viability and Function of Hippocampal Neurons in Adult Mice.

The unfolded protein response (UPR), which comprises three branches: PERK, ATF6α, and IRE1, is a major mechanism for maintaining cellular proteostasis. Many studies show that the UPR is a major player in regulating neuron viability and function in various neurodegenerative diseases; however, its role in neurodegeneration is highly controversial. Moreover, while evidence suggests activation of the UPR in neurons under normal conditions, deficiency of individual branches of the UPR has no major effect on brain neurons in animals. It remains unclear whether or how the UPR participates in regulating neuronal proteostasis under normal and disease conditions. To determine the physiological role of the UPR in neurons, we generated mice with double deletion of PERK and ATF6α in neurons. We found that inactivation of PERK and ATF6α in neurons caused lysosomal dysfunction (as evidenced by decreased expression of the V0a1 subunit of v-ATPase and decreased activation of cathepsin D), impairment of autophagic flux (as evidenced by increased ratio of LC3-II/LC3-I and increased p62 level), and accumulation of p-tau and Aß42 in the hippocampus, and led to impairment of spatial memory, impairment of hippocampal LTP, and hippocampal degeneration in adult mice. These results suggest that the UPR is required for maintaining neuronal proteostasis (particularly tau and Aß homeostasis) and the viability and function of neurons in the hippocampus of adult mice.

Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery.

As a minimally invasive drug delivery platform, microneedles (MNs) overcome many drawbacks of the conventional transdermal drug delivery systems, therefore are favorable in biomedical applications. Microneedles with a combined burst and sustained release profile and maintained therapeutic molecular bioactivity could further broaden its applications as therapeutics. Here, we developed a double-network microneedles (DN MNs) based on gelatin methacrylate and acellular neural matrix (GelMA-ACNM). ACNM could function as an early drug release matrix, whereas the addition of GelMA facilitates sustained drug release. In particular, the double-network microneedles comprising GelMA-ACNM hydrogel has distinctive biological features in maintaining drug activity to meet the needs of application in treating different diseases. In this study, we prepared the double-network microneedles and evaluated its morphology, mechanical properties, drug release properties and biocompatibility, which shows great potential for delivery of therapeutic molecules that needs different release profiles in transdermal treatment.

Endoplasmic reticulum associated degradation is essential for maintaining the viability or function of mature myelinating cells in adults.

Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1LloxP/loxP mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS. Because Sel1L is deleted in myelinating cells of CNP/Cre; Sel1LloxP/loxP mice starting at very early stage of differentiation, it is impossible to rule out the possibility that the adult-onset myelin abnormalities in these mice results from developmental myelination defects caused by Sel1L knockout in myelinating cells during development. Thus, using an inducible Sel1L knockout mouse model (PLP/CreERT ; Sel1LloxP/loxP mice) that has normal, intact myelin and myelinating cells in the adult CNS and PNS prior to tamoxifen treatment, we sought to determine if Sel1L knockout in mature myelinating cells of adult mice leads to myelin abnormalities in the CNS and PNS. We showed that Sel1L knockout in mature myelinating cells caused ERAD impairment, ER stress and UPR activation. Interesting, Sel1L knockout in mature oligodendrocytes impaired their myelinating function by suppressing myelin protein translation, and resulted in progressive myelin thinning in the adult CNS. Conversely, Sel1L knockout in mature Schwann cells led to Schwann cell apoptosis and demyelination in the adult PNS. These findings demonstrate the essential roles of ERAD in mature myelinating cells in the adult CNS and PNS under physiological conditions.

A Silicone Resin Coating with Water-Repellency and Anti-Fouling Properties for Wood Protection.

The strong hygroscopicity of wood greatly shortens its service life. Here, a simple impregnation modification approach was used to construct superhydrophobic silicone resin coatings on wood surfaces. Briefly, with hydrofluorosilicone oil (HFSO), tetramethyl tetravinyl cyclotetrasiloxane (V4), and hydrophobic SiO2 from industrial production as raw materials, superhydrophobic wood samples (water contact angle ~160.8°, sliding angle ~3.6°) can be obtained by simply dipping the wood in the HFSO/V4/SiO2 modifier solutions. As a result, the superhydrophobic silicone resin coating constructed on the wood surface still has good water repellency after finger touching, tape peeling, and sandpaper abrasion. When the mass ratio of HFSO to V4 is 2:1, the water absorption of the resulting wood after soaking in water for 24 h is only 29.2%. Further, the resulting superhydrophobic wood shows excellent anti-fouling properties. Finally, we believe that the impregnation modification method proposed in this study can be applied to the protection of cellulose substrates.

Facile Fabrication of Fluorine-Free, Anti-Icing, and Multifunctional Superhydrophobic Surface on Wood Substrates.

Building superhydrophobic protective layers on the wood substrates is promising in terms of endowing them with multiple functions, including water-repellent, self-cleaning, anti-icing functions. In this study, multifunctional superhydrophobic wood was successfully fabricated by introducing SiO2 sol and superhydrophobic powder (PMHOS). The SiO2 sol was prepared using tetraethoxysilane as a precursor and ethanol was used as the dispersant. The PMHOS was synthesized using poly(methylhydrogen)siloxane (PMHS) and ethanol. As a result, the obtained superhydrophobic wood had a water contact angle (WCA) of 156° and a sliding angle (SA) of 6° at room temperature. The obtained superhydrophobic wood exhibited excellent repellency toward common liquid (milk, soy sauce, juice, and coffee). The superhydrophobic layer on the wood surface also exhibited good durability after a series of mechanical damages, including finger wiping, tape peeling, knife scratching, and sandpaper abrasion. In addition, the obtained superhydrophobic wood showed excellent anti-icing properties.

Detection of PERK Signaling in the Central Nervous System.

In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) signaling adapts cells to stressful conditions by phosphorylating eukaryotic translation initiation factor 2α (eIF2α). Phosphorylation of eIF2α inhibits global protein translation but stimulates the expression of numerous stress-responsive genes by inducing the transcription factor ATF4. A large number of studies have shown that activation of PERK signaling has beneficial or detrimental effects in various diseases of the central nervous system (CNS), including neurodegenerative diseases, myelin disorders, CNS injuries, among others. This chapter is devoted to describing the practical methods for the detection of PERK signaling in CNS diseases.

Electrospun Fibers Derived from Peptide Coupled Amphiphilic Copolymers for Dorsal Root Ganglion (DRG) Outgrowth.

Developing scaffolds with appropriate mechanical/structural features as well as tunable bioactivities are indispensable in the field of tissue engineering. This study focused on one such attempt to electrospin the copolymer of L-lactic acid (L-LA) and functional monomer (3(S)- [(benzyloxycarbony)methyl]-1,4-dioxane-2,5-dione, BMD) with small peptide modifications for the purpose of neural tissue engineering. Scanning Electron Microscopy (SEM) micrographs showed fabricated electrospun copolymer as porous and uniform nanofibrous materials with diameter in the range of 800-1000 nm. In addition, the modified scaffolds displayed a lower contact angle than poly(L-lactide) (PLLA) indicating higher hydrophilicity. To further incorporate the bioactive functions, the nanofibers were chemically coupled with small peptide (isoleucine-lysine-valine-alanine-valine, IKVAV). The incorporation of IKVAV onto the electrospun fiber was confirmed by X-ray photoelectron spectroscopy (XPS) and such incorporation did not affect the surface morphology or fiber diameters. To demonstrate the potential of applying the designed scaffolds for nerve regeneration, dorsal root ganglion (DRG) neurons were cultured on the nanofibers to examine the impact on neurite outgrowth of DRGs. The results indicated that the fabricated nanofibrous matrix with small peptide might be a potential candidate for neural tissue engineering.

Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults.

The integrated unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) is the principle mechanisms that maintain endoplasmic reticulum (ER) homeostasis. Schwann cells (SCs) must produce an enormous amount of myelin proteins via the ER to assemble and maintain myelin structure; however, it is unclear how SCs maintain ER homeostasis. It is known that Suppressor/Enhancer of Lin-12-like (Sel1L) is necessary for the ERAD activity of the Sel1L- hydroxymethylglutaryl reductase degradation protein 1(Hrd1) complex. Herein, we showed that Sel1L deficiency in SCs impaired the ERAD activity of the Sel1L-Hrd1 complex and led to ER stress and activation of the UPR. Interestingly, Sel1L deficiency had no effect on actively myelinating SCs during development, but led to later-onset mature SC apoptosis and demyelination in the adult PNS. Moreover, inactivation of the pancreatic ER kinase (PERK) branch of the UPR did not influence the viability and function of actively myelinating SCs, but resulted in exacerbation of ER stress and apoptosis of mature SCs in SC-specific Sel1L deficient mice. These findings suggest that the integrated UPR and ERAD is dispensable to actively myelinating SCs during development, but is necessary for maintaining ER homeostasis and the viability and function of mature SCs in adults.

The Integrated UPR and ERAD in Oligodendrocytes Maintain Myelin Thickness in Adults by Regulating Myelin Protein Translation.

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.SIGNIFICANCE STATEMENT Myelin is an enormous extended plasma membrane of oligodendrocytes that wraps and insulates axons. Myelin structure, including thickness, was thought to be extraordinarily stable in adults. Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfolded protein response (UPR) and ER-associated degradation (ERAD) are the primary mechanism that maintains ER protein homeostasis. Herein, we explored the role of the integrated UPR and ERAD in oligodendrocytes in regulating myelin protein production and maintaining myelin structure using mouse models. The results presented in this study imply that the integrated UPR and ERAD in oligodendrocytes maintain myelin thickness in adults by regulating myelin protein production.

Distinct promoter methylation patterns of LKB1 in the hamartomatous polyps of Peutz-Jeghers syndrome and its potential in gastrointestinal malignancy prediction.

BACKGROUND: Peutz-Jeghers Syndrome (PJS) is known as a rare inherited polyposis due to the malfunction of serine/threonine kinase gene LKB1. However, not all of PJS patients carry LKB1 germline mutation. Previous researches have observed the elevated DNA methylation level in PJS polyps. Nevertheless, the mechanism of such abnormal and its impact on PJS patients remains to be fully described. RESULTS: The results proved a significant increase on the methylation level of LKB1 promoter in PJS polyps compared with normal colon biopsies through bisulfite PCR followed by Sanger sequencing. Moreover, the methylation pattern in PJS polyps could be further categorized as three different scenarios: hypermethylated, hemimethylated and hypomethylated pattern. Furthermore, immunohistochemistry of DNMT1/3a/3b suggested the up-regulation of DNMT1 and 3a might participate the epigenetic alternation of LKB1 in PJS polyps. Logistic regression suggested hypomethylated LKB1 promoter in PJS polyps as a risk factor for gastrointestinal malignancies in PJS patients. CONCLUSIONS: The promoter methylation level of LKB1 gene in PJS polyps is generally elevated compared with normal colon mucosa. Yet not all of PJS polyps carry hypermethylated LKB1 promoter. Hypomethylation in this region has linked to malignant tumors in PJS patients. Given the rarity of PJS, this work together with previous researches, have proved the importance of LKB1 promoter methylation in PJS development and prognosis.

NF-κB Activation Accounts for the Cytoprotective Effects of PERK Activation on Oligodendrocytes during EAE.

Previous studies demonstrate that activation of pancreatic ER kinase (PERK) protects oligodendrocytes against inflammation in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Interestingly, data indicate that the cytoprotective effects of PERK activation on oligodendrocytes during EAE are not mediated by activating transcription factor 4 (ATF4) but are accompanied by activation of nuclear factor κB (NF-κB). NF-κB plays a critical role in MS and EAE; however, the effects of NF-κB activation on oligodendrocytes in these diseases remain elusive. Herein, we generated a mouse model that allow for activation of NF-κB specifically in oligodendrocytes and found that enhanced NF-κB activation in oligodendrocytes had a minimal effect on their viability and function under normal conditions (both male and female mice). Interestingly, we found that enhanced NF-κB activation in oligodendrocytes attenuated EAE disease severity and ameliorated EAE-induced oligodendrocyte loss, demyelination, and axon degeneration, without affecting inflammation (female mice). Moreover, we showed that the detrimental effects of PERK inactivation in oligodendrocytes in EAE were accompanied by impaired NF-κB activation in oligodendrocytes, and were completely rescued by enhanced NF-κB activation in oligodendrocytes (female mice). These findings suggest that NF-κB activation accounts for the cytoprotective effects of PERK activation on oligodendrocytes in MS and EAE.SIGNIFICANCE STATEMENT Nuclear factor κB (NF-κB) is activated in oligodendrocytes in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE); however, the role of NF-κB activation in oligodendrocytes in MS and EAE remains elusive. Herein, we generated a mouse model that allows for activation of NF-κB selectively in oligodendrocytes and demonstrated that NF-κB activation prevented oligodendrocyte death and myelin damage in the EAE model. We further demonstrated that NF-κB activation contributed to the protective effects of pancreatic ER kinase (PERK) activation on oligodendrocytes in the EAE model. As such, this work will facilitate the development of new treatments that enhance oligodendrocyte survival in MS patients by targeting the PERK-NF-κB pathway.

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP.

Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. Unfolded protein response (UPR), which comprises 3 parallel branches, inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6α (ATF6α), is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ER-associated degradation. Here we report that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination but caused late-onset mature oligodendrocyte dysfunction and death in young adult mice. The detrimental effects of the impaired UPR on mature oligodendrocytes were accompanied by autophagy impairment and intracellular proteolipid protein (PLP) accumulation and were rescued by PLP deletion. Data indicate that PLP was degraded by autophagy and that intracellular PLP accumulation was cytotoxic to oligodendrocytes. Thus, these findings imply that the UPR is required for maintaining cellular proteostasis and the viability and function of mature oligodendrocytes in adults by regulating autophagy of PLP.

Environment-Friendly and Two-Component Method for Fabrication of Highly Hydrophobic Wood Using Poly(methylhydrogen)siloxane.

Practical application of wood remains a great challenge because of its highly hydrophilic property. In this work, highly hydrophobic wood was produced using an environment-friendly and two-component package method. Poly(methylhydrogen)siloxane (PMHS) and inhibitor played the key role in the hydrophobicity of wood and the assembly process. The two-component package mechanism was discussed in detail. As a result, the water contact angles of the modified wood surface for the radial and cross sections were 139.5° and 152.9°, respectively, which provided the resultant wood high hydrophobicity and dimensional stability. The two-component package method afforded the wood good anti-fouling property and UV-resistance. In addition, the two-component package method could also be applied in functionalization of filter paper for oil/water separation.

Unfolded protein response in myelin disorders.

Activation of the unfolded protein response in response to endoplasmic reticulum stress preserves cell viability and function under stressful conditions. Nevertheless, persistent, unresolvable activation of the unfolded protein response can trigger apoptosis to eliminate stressed cells. Recent studies show that the unfolded protein response plays an important role in the pathogenesis of various disorders of myelin, including multiples sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, vanishing white matter disease, spinal cord injury, tuberous sclerosis complex, and hypoxia-induced perinatal white matter injury. In this review we summarize the current literature on the unfolded protein response and the evidence for its role in the pathogenesis of myelin disorders.

Formononetin attenuates monocrotaline­induced pulmonary arterial hypertension via inhibiting pulmonary vascular remodeling in rats.

Pulmonary arterial hypertension (PAH) is a life­threatening disease induced by the excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Formononetin (FMN) is a natural isoflavone with numerous cardioprotective properties, which can inhibit the proliferation and induce the apoptosis of tumor cells; however, whether FMN has a therapeutic effect on PAH remains unclear. In the present study, PAH was induced in rats with monocrotaline (MCT, 60 mg/kg); rats were then administered FMN (10, 30 or 60 mg/kg/day). At the end of the experiment, hemodynamic changes, right ventricular hypertrophy and lung morphological characteristics were evaluated. α­smooth muscle actin (α­SMA), proliferating cell nuclear antigen (PCNA), and TUNEL were detected by immunohistochemical staining. The expression of PCNA, Bcl­2­associated X protein (Bax), Bcl­2 and, cleaved caspase­3, and activation of AKT and ERK were examined by western blot analysis. The results demonstrated that FMN significantly ameliorated the right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling induced by MCT. FMN also attenuated MCT­induced increased expression of α­SMA and PCNA. The ratio of Bax/Bcl­2 and cleaved caspase­3 expression increased in rat lung tissue in response to FMN treatment. Furthermore, reduced phosphorylation of AKT and ERK was also observed in FMN­treated rats. Therefore, FMN may provide protection against MCT­induced PAH by preventing pulmonary vascular remodeling, potentially by suppressing the PI3K/AKT and ERK pathways in rats.

Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE.

BACKGROUND: Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating and neurodegenerative diseases of the CNS. Although recent studies suggest the neuroprotective effects of oligodendrocytes in neurodegenerative diseases, it remains unknown whether oligodendrocyte death induced by inflammatory attacks contributes to neurodegeneration in MS and EAE. Upon endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) promotes cell survival through induction of activating transcription factor 4 (ATF4) by phosphorylating eukaryotic translation initiation factor 2α (eIF2α). We have generated a mouse model that allows for temporally controlled activation of PERK specifically in oligodendrocytes. Our previous study has demonstrated that PERK activation specifically in oligodendrocytes attenuates EAE disease severity and ameliorates EAE-induced oligodendrocyte apoptosis, demyelination, and axon degeneration, without altering inflammation. METHODS: We determined whether oligodendrocyte-specific PERK activation reduced neuron loss in the CNS of EAE mice using the mouse model that allows for temporally controlled activation of PERK specifically in oligodendrocytes. We further generated a mouse model that allows for inactivation of ATF4 specifically in oligodendrocytes, and determined the effects of ATF4 inactivation in oligodendrocytes on mice undergoing EAE. RESULTS: We showed that protection of oligodendrocytes resulting from PERK activation led to attenuation of neuron loss in the CNS gray matter of EAE mice. Surprisingly, we found that ATF4 inactivation specifically in oligodendrocytes did not alter EAE disease severity and had no effect on oligodendrocyte loss, demyelination, axon degeneration, neuron loss, and inflammation in EAE mice. CONCLUSIONS: These findings suggest the neuroprotective effects of PERK activation in oligodendrocytes in EAE, and rule out the involvement of ATF4 in oligodendrocytes in the development of EAE. These results imply that the protective effects of PERK activation in oligodendrocytes in MS and EAE are not mediated by ATF4.

Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis.

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.