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.

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.

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.

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.

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.

Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis.

Multiple sclerosis is a chronic autoimmune demyelinating disorder of the CNS. Immune-mediated oligodendrocyte cell loss contributes to multiple sclerosis pathogenesis, such that oligodendrocyte-protective strategies represent a promising therapeutic approach. The integrated stress response, which is an innate cellular protective signalling pathway, reduces the cytotoxic impact of inflammation on oligodendrocytes. This response is initiated by phosphorylation of eIF2α to diminish global protein translation and selectively allow for the synthesis of protective proteins. The integrated stress response is terminated by dephosphorylation of eIF2α. The small molecule Sephin1 inhibits eIF2α dephosphorylation, thereby prolonging the protective response. Herein, we tested the effectiveness of Sephin1 in shielding oligodendrocytes against inflammatory stress. We confirmed that Sephin1 prolonged eIF2α phosphorylation in stressed primary oligodendrocyte cultures. Moreover, by using a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrated that Sephin1 delayed the onset of clinical symptoms, which correlated with a prolonged integrated stress response, reduced oligodendrocyte and axon loss, as well as diminished T cell presence in the CNS. Sephin1 is reportedly a selective inhibitor of GADD34 (PPP1R15A), which is a stress-induced regulatory subunit of protein phosphatase 1 complex that dephosphorylates eIF2α. Consistent with this possibility, GADD34 mutant mice presented with a similar ameliorated experimental autoimmune encephalomyelitis phenotype as Sephin1-treated mice, and Sephin1 did not provide additional therapeutic benefit to the GADD34 mutant animals. Results presented from the adoptive transfer of encephalitogenic T cells between wild-type and GADD34 mutant mice further indicate that the beneficial effects of Sephin1 are mediated through a direct protective effect on the CNS. Of particular therapeutic relevance, Sephin1 provided additive therapeutic benefit when combined with the first line multiple sclerosis drug, interferon ß. Together, our results suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients.

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.

NF-κB Activation Protects Oligodendrocytes against Inflammation.

NF-κB is a key player in inflammatory diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the effects of NF-κB activation on oligodendrocytes in MS and EAE remain unknown. We generated a mouse model that expresses IκBαΔN, a super-suppressor of NF-κB, specifically in oligodendrocytes and demonstrated that IκBαΔN expression had no effect on oligodendrocytes under normal conditions (both sexes). Interestingly, we showed that oligodendrocyte-specific expression of IκBαΔN blocked NF-κB activation in oligodendrocytes and resulted in exacerbated oligodendrocyte death and hypomyelination in young, developing mice that express IFN-γ ectopically in the CNS (both sexes). We also showed that NF-κB inactivation in oligodendrocytes aggravated IFN-γ-induced remyelinating oligodendrocyte death and remyelination failure in the cuprizone model (male mice). Moreover, we found that NF-κB inactivation in oligodendrocytes increased the susceptibility of mice to EAE (female mice). These findings imply the cytoprotective effects of NF-κB activation on oligodendrocytes in MS and EAE.SIGNIFICANCE STATEMENT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. NF-κB is a major player in inflammatory diseases that acts by regulating inflammation and cell viability. Data indicate that NF-κB activation in inflammatory cells facilitates the development of MS. However, to date, attempts to understand the role of NF-κB activation in oligodendrocytes in MS have been unsuccessful. Herein, we generated a mouse model that allows for inactivation of NF-κB specifically in oligodendrocytes and then used this model to determine the precise role of NF-κB activation in oligodendrocytes in models of MS. The results presented in this study represent the first demonstration that NF-κB activation acts cell autonomously to protect oligodendrocytes against inflammation in animal models of MS.

Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro-inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed-induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-γ-expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases.

ZFP191 is required by oligodendrocytes for CNS myelination.

The controlling factors that prompt mature oligodendrocytes to myelinate axons are largely undetermined. In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 (Zfp191), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein-protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function. Therefore, this study demonstrates that ZFP191 is required for the myelinating function of differentiated oligodendrocytes.

PERK Activation Promotes Medulloblastoma Tumorigenesis by Attenuating Premalignant Granule Cell Precursor Apoptosis.

Evidence suggests that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress negatively or positively influences cell transformation by regulating apoptosis. Patched1 heterozygous deficient (Ptch1(+/-)) mice reproduce human Gorlin's syndrome and are regarded as the best animal model to study tumorigenesis of the sonic hedgehog subgroup of medulloblastomas. It is believed that medulloblastomas in Ptch1(+/-) mice results from the transformation of granule cell precursors (GCPs) in the developing cerebellum. Here, we determined the role of PERK signaling on medulloblastoma tumorigenesis by assessing its effects on premalignant GCPs and tumor cells. We found that PERK signaling was activated in both premalignant GCPs in young Ptch1(+/-) mice and medulloblastoma cells in adult mice. We demonstrated that PERK haploinsufficiency reduced the incidence of medulloblastomas in Ptch1(+/-) mice. Interestingly, PERK haploinsufficiency enhanced apoptosis of premalignant GCPs in young Ptch1(+/-) mice but had no significant effect on medulloblastoma cells in adult mice. Moreover, we showed that the PERK pathway was activated in medulloblastomas in humans. These results suggest that PERK signaling promotes medulloblastoma tumorigenesis by attenuating apoptosis of premalignant GCPs during the course of malignant transformation.

A Distance Detector with a Strip Magnetic MOSFET and Readout Circuit.

This paper presents a distance detector composed of two separated metal-oxide semiconductor field-effect transistors (MOSFETs), a differential polysilicon cross-shaped Hall plate (CSHP), and a readout circuit. The distance detector was fabricated using 0.18 µm 1P6M Complementary Metal-Oxide Semiconductor (CMOS) technology to sense the magnetic induction perpendicular to the chip surface. The differential polysilicon CSHP enabled the magnetic device to not only increase the magnetosensitivity but also eliminate the offset voltage generated because of device mismatch and Lorentz force. Two MOSFETs generated two drain currents with a quadratic function of the differential Hall voltages at CSHP. A readout circuit-composed of a current-to-voltage converter, a low-pass filter, and a difference amplifier-was designed to amplify the current difference between two drains of MOSFETs. Measurements revealed that the electrostatic discharge (ESD) could be eliminated from the distance sensor by grounding it to earth; however, the sensor could be desensitized by ESD in the absence of grounding. The magnetic influence can be ignored if the magnetic body (human) stays far from the magnetic sensor, and the measuring system is grounded to earth by using the ESD wrist strap (Strap E-GND). Both 'no grounding' and 'grounding to power supply' conditions were unsuitable for measuring the induced Hall voltage.

High Performance CMOS Light Detector with Dark Current Suppression in Variable-Temperature Systems.

This paper presents a dark current suppression technique for a light detector in a variable-temperature system. The light detector architecture comprises a photodiode for sensing the ambient light, a dark current diode for conducting dark current suppression, and a current subtractor that is embedded in the current amplifier with enhanced dark current cancellation. The measured dark current of the proposed light detector is lower than that of the epichlorohydrin photoresistor or cadmium sulphide photoresistor. This is advantageous in variable-temperature systems, especially for those with many infrared light-emitting diodes. Experimental results indicate that the maximum dark current of the proposed current amplifier is approximately 135 nA at 125 °C, a near zero dark current is achieved at temperatures lower than 50 °C, and dark current and temperature exhibit an exponential relation at temperatures higher than 50 °C. The dark current of the proposed light detector is lower than 9.23 nA and the linearity is approximately 1.15 µA/lux at an external resistance RSS = 10 kΩ and environmental temperatures from 25 °C to 85 °C.

Impaired eukaryotic translation initiation factor 2B activity specifically in oligodendrocytes reproduces the pathology of vanishing white matter disease in mice.

Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features of VWMD pathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2α, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.

PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis.

There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. Moreover, there is evidence that PERK signaling is activated in oligodendrocytes within demyelinating lesions in multiple sclerosis and EAE. Our previous study demonstrated that CNS delivery of the inflammatory cytokine interferon-γ before EAE onset protected mice against EAE, and this protection was dependent on PERK signaling. In our current study, we sought to elucidate the role of PERK signaling in oligodendrocytes during EAE. We generated transgenic mice that allow for temporally controlled activation of PERK signaling, in the absence of ER stress, specifically in oligodendrocytes. We demonstrated that persistent activation of PERK signaling was not deleterious to oligodendrocyte viability or the myelin of adult animals. Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.

Thermoresponsive fluorescence of a graphene-polymer composite based on a local surface plasmon resonance effect.

A water-processable blue fluorescent silver nanoparticle@graphene-polymer composite (Ag@G-pNIPAM) consisting of graphene coated with a thermally responsive poly-(N-isopropylacrylamide) (pNIPAM) shell is prepared. The pNIPAM shell swells or collapses as a function of temperature, serving as a means to trap silver nanoparticles in solution and get them sufficiently close to the graphene core to provide fluorescence enhancement based on the local surface plasmon resonance (LSPR) effect. The unique thermoresponsive properties and high enhancement ratio of the material should find application in solution fluorescence enhancers and a variety of biomedical applications, such as cellular uptake, sensing and imaging.

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 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.

Endoplasmic reticulum associated degradation preserves neurons viability by maintaining endoplasmic reticulum homeostasis.

Endoplasmic reticulum-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. Evidence suggests that impairment of ERAD contributes to neuron dysfunction and death in neurodegenerative diseases, many of which are characterized by accumulation and aggregation of misfolded proteins. However, the physiological role of ERAD in neurons remains unclear. The Sel1L-Hrd1 complex consisting of the E3 ubiquitin ligase Hrd1 and its adaptor protein Sel1L is the best-characterized ERAD machinery. Herein, we showed that Sel1L deficiency specifically in neurons of adult mice impaired the ERAD activity of the Sel1L-Hrd1 complex and led to disruption of ER homeostasis, ER stress and activation of the unfold protein response (UPR). Adult mice with Sel1L deficiency in neurons exhibited weight loss and severe motor dysfunction, and rapidly succumbed to death. Interestingly, Sel1L deficiency in neurons caused global brain atrophy, particularly cerebellar and hippocampal atrophy, in adult mice. Moreover, we found that cerebellar and hippocampal atrophy in these mice resulted from degeneration of Purkinje neurons and hippocampal neurons, respectively. These findings indicate that ERAD is required for maintaining ER homeostasis and the viability and function of neurons in adults under physiological conditions.