Ipsilateral simultaneous multiple hypertensive intracerebral hemorrhages: Analysis of hematoma formation and comparison with distribution of hypertensive mixed-type hematoma.

A 55-year-old Japanese woman with a history of hypertension and right putaminal hemorrhage developed simultaneous hemorrhages in the left thalamus and putamen and died 24 h later. There were no vascular anomalies in the brain. Synaptophysin immunostaining combined with eosin azure 50 (EA50) staining clearly identified the hematoma and the surrounding brain structures. In the right cerebral hemisphere, a cystic lesion as a sequela of the usual type of hypertensive putaminal hematoma was evident. In the left cerebral hemisphere, two fresh hematomas were evident. One was a thalamic hematoma, which had destroyed the dorsal and medial structures of the thalamus, and the other was an unusual putaminal hematoma, which had destroyed the entire putamen and crossed the internal capsule and caudate nucleus. α-Smooth muscle actin immunostaining combined with EA50 and Victoria bleu staining demonstrated three ruptured arteries associated with fibrin aggregates in the anterior thalamic nucleus and anterior putamen. Some circular structures composed of fibrin, suggesting the presence of ruptured arteries in the neighborhood, were evident in the thalamus and putamen. In the putamen, ruptured arteries and circular structures were present in the lateral to medial areas. Fibrin aggregates in the anterior thalamic nucleus were more numerous than those in the putamen. On the basis of these findings, we concluded that: (i) the artery with numerous fibrin aggregates in the anterior thalamic nucleus had ruptured first, followed by the arteries distributed in other parts of the thalamus and putamen; (ii) the unusual putaminal hematoma was attributable to rupture of the arteries around the center of the putamen, which are not responsible for the usual type of hypertensive putaminal hematoma; and (iii) it is suggested that even if hypertensive hemorrhage occurs simultaneously in the ipsilateral putamen and thalamus, the usual type of hypertensive mixed-type hematoma does not form.

Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Liver Abscess due to Streptococcus intermedius Bacteremia and Its Association with Colonic Carcinoma: Is Bacteremia with Streptococcus intermedius an Alert for Colonic Carcinoma?

Liver abscess caused by some kinds of Streptococcus group such as Streptococcus bovis group has been recognized to associate with colorectal cancer. Streptococcus milleri group with liver abscess has not been received much attention in this point of view. Here, we report the case of a 63-year-old man who developed liver abscess with S. intermedius, which belongs to the S. milleri group. We confirmed that this case was accompanied by cecal carcinoma by colonoscopy. The tumor was a pathological lead point of intussusception of cecum. On the 26th day, open right hemicolectomy was performed. In this case, bacterial endophthalmitis was a complication due to bacteremia. The patient underwent ophthalmic surgery on the 98th day. Research investigating 16S rRNA of the mucosal colon microbiome reported that the S. intermedius gene was upregulated in patients with colorectal carcinoma. It is recommended that liver abscess with S. intermedius bacteremia should alert the clinician about the risks of carcinoma of the colon and abscess formation in distant organs. We here list the case reports of liver abscess caused by Streptococcus other than S. bovis group, which was associated with colonic carcinoma, and suggest the need for further research about S. milleri group.

Evidence of impaired macroautophagy in human degenerative cervical myelopathy.

Degenerative cervical myelopathy (DCM) is a common progressive disease of the spinal cord which can cause tetraplegia. Despite its prevalence, few studies have investigated the pathophysiology of DCM. Macroautophagy is a cellular process which degrades intracellular contents and its disruption is thought to contribute to many neurodegenerative diseases. The present study tests the hypothesis that macroautophagy is impaired in DCM. To address this, we utilised a collection of post-mortem cervical spinal cord samples and investigated seven DCM cases and five human controls. Immunohistochemical staining was used to visualise proteins involved in autophagy. This demonstrated significantly reduced numbers of LC3 puncta in cases versus controls (p = 0.0424). Consistent with reduced autophagy, we identified large aggregates of p62 in four of seven cases and no controls. Tau was increased in two of five cases compared to controls. BCL-2 was significantly increased in cases versus controls (p = 0.0133) and may explain this reduction in autophagy. Increased BCL-2 (p = 0.0369) and p62 bodies (p = 0.055) were seen in more severe cases of DCM. This is the first evidence that autophagy is impaired in DCM; the impairment appears greater in more severe cases. Further research is necessary to investigate whether macroautophagy has potential as a therapeutic target in DCM.

Changes in virus detection in hospitalized children before and after the severe acute respiratory syndrome coronavirus 2 pandemic.

The impact of strengthening preventive measures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the prevalence of respiratory viruses in children was examined. After the SARS-CoV-2 pandemic, the rate of multiple virus detection among hospitalized children decreased. Immediately after the SARS-CoV-2 pandemic, respiratory syncytial and parainfluenza viruses were rarely detected and subsequently reemerged. Human metapneumovirus and influenza virus were not consistently detected. Non-enveloped viruses (bocavirus, rhinovirus, and adenovirus) were detected to some extent even after the pandemic. Epidemic-suppressed infectious diseases may reemerge as susceptibility accumulates in the population and should continue to be monitored.

Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.

EGFRvIII Is Expressed in Cellular Areas of Tumor in a Subset of Glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface antigen often expressed in glioblastoma and has drawn much attention as a possible therapeutic target. We performed immunohistochemistry on histology sections of surgical specimens taken from 67 cases with glioblastoma, isocitrate dehydrogenase-wild type, and evaluated the morphological characteristics and distribution of the EGFRvIII-positive tumor cells. We then evaluated the localization of EGFRvIII-expression within the tumor and peritumoral areas. EGFRvIII immunopositivity was detected in 15 specimens taken from 13 patients, including two recurrent specimens taken from the same patient at relapse. Immunofluorescence staining demonstrated that EGFRvIII-positive cells were present in cells positive for glial fibrillary acidic protein (GFAP), and some showed astrocytic differentiation with multiple fine processes and others did not shown. The EGFRvIII-positive cells were located in cellular areas of the tumor, but not in the invading zone. In the two recurrent cases, EGFRvIII-positive cells were markedly decreased in one case and retained in the other. With regard to overall survival, univariate analysis indicated that EGFRvIII-expression in patients with glioblastoma was not significantly associated with a favorable outcome. Double-labeling immunofluorescence staining of EGFRvIII and GFAP showed that processes of large, well differentiated, GFAP-positive glia extend to and surround less differentiated, EGFRvIII-positive glial cells in cellular areas of tumor. However, in the tumor periphery, EGFRvIII-positive tumor cells were not observed. This finding suggests that EGFRvIII is involved in tumor proliferation, but that invading glioma cells lose their EGFRvIII expression.

Clinicopathologic Features of Two Patients With Sporadic Amyotrophic Lateral Sclerosis Who Maintained Communication Ability for Over 30 Years.

We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging.

Neurodegenerative disorders such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by impairment of autophagy. Cellular survival is dependent on efficient clearance of phosphorylated α-synuclein, which accumulates as fibrils in the neuronal cytoplasm as Lewy bodies (LBs). The forkhead box O 1 (FOXO1) is a member of the FOXO family that functions in various intracellular processes including regulation of autophagy. Transcriptional activation of FOXO1 has been reported to initiate autophagy by inhibiting the expression of Mechanistic Target of Rapamycin (mTOR), mediated by sestrin 3 (SESN3) and tuberous sclerosis complex 2 (TSC2). Although many autophagy-related proteins are known to be incorporated into LBs, no report has documented the involvement of these autophagy modulators (FOXO1, SESN3 and TSC2) in the pathogenesis of PD and DLB. In the present study, we performed immunostaining and Western blot analysis using the brains of normal controls and patients with PD and DLB in order to clarify the involvement of FOXO1, SESN3 and TSC2 in LBs. Our study demonstrated for the first time the presence of FOXO1, SESN3 and TSC2 in brainstem-type LBs. The expression levels of these proteins in the brain did not differ between the normal controls and patients with PD or DLB. We further utilized mice model to investigate the effect of α-synuclein overexpression on these proteins, and found that TSC2 was significantly increased in α-synuclein transgenic mice relative to wild type mice at 9 weeks of age, but not at 30 weeks of age. Together with expression data showing gradual increase of these molecules with age in wild type mice, these findings suggest that autophagy modulators are incorporated into LBs and that the expression of these proteins can be increased by various factors including aging.

Effects of the -141C insertion/deletion polymorphism in the dopamine D2 receptor gene on the dopamine system in the striatum in patients with schizophrenia.

The relationships between -141C insertion/deletion (Ins/Del) polymorphisms in the dopamine D2 receptor gene and the two dopamine system integrators, i.e., dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN), are still unclear. In this study, we assessed the effect of this polymorphism on DARPP-32 and CaN protein expression in the postmortem striatum of patients with schizophrenia and control individuals. The expression levels of truncated DARPP and CaN were lower in Del allele carriers. These findings provide important insights into the mechanism by which this genotype could result in a poor response to antipsychotic drugs.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity.

Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells. However, it has remained unclear whether YOD1 is associated with pathophysiological conditions such as mitochondrial damage, impaired proteostasis, and neurodegeneration. We demonstrated that YOD1 possesses deubiquitinating activity and exhibits preference for K48- and K63-linked ubiquitin. Furthermore, YOD1 expression levels increased as a result of various stress conditions. We demonstrated that the neurogenic proteins that cause Huntington disease and Parkinson's disease induced upregulation of YOD1 level. We observed that YOD1 reduced disease cytotoxicity through efficient degradation of mutant proteins, whereas this activity was abolished by catalytically inactive YOD1. Additionally, YOD1 localized to Lewy bodies in Parkinson's disease patients. Collectively, these data suggest that the deubiquitinase YOD1 contributes to pathogenesis of neurodegenerative disease by decreasing ubiquitination of abnormal proteins and their subsequent degradation.

The perivascular microenvironment in Epstein-Barr virus positive primary central nervous system lymphoma: The role of programmed cell death 1 and programmed cell death ligand 1.

It has been shown that high expression of certain immune checkpoint molecules, including those of the programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis, can be utilized to regulate immunosuppression in the microenvironment of malignant neoplasms. For the purpose of clarifying the immune-escape mechanism of primary central nervous system lymphomas (PCNSLs), particularly in Epstein-Barr virus (EBV)-positive cases, markers for PD-1, PD-L1, tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in 39 surgical specimens of PCNSLs (17 EBV-positive, 22 EBV-negative) were investigated by immunohistochemistry. Staining for PD-L1 was scored as follows: (-), no staining; (1+), 0-30% positive cells; (2+), 30-60% positive cells; and (3+), >60% positive cells. In EBV-positive cases, PD-L1 was detected in both lymphoma cells and TAMs in 12/17 cases, and in TAMs only in 4/17 cases. The mean number of PD-1, TIA-1 (a marker for cytotoxic T-cells), and FOXP3 (a marker for regulatory T-cells)-positive TILs in EBV-positive cases was 36.4 ± 45.9, 390 ± 603, and 9.88 ± 15.1, respectively. In EBV-negative cases, PD-L1 was detected in both lymphoma cells and TAMs in 11/22 cases, and in TAMs only in 4/22 cases. The mean of PD-1, TIA-1 and FOXP3-positive lymphocytes in EBV-negative cases was 67.3 ± 82.0, 158 ± 206 and 9.32 ± 17.5, respectively. We found no significant difference in the number of FOXP3-positive, lymphocytes between EBV-positive and negative cases. However, there were significantly higher numbers of PD-1-positive lymphocytes in the former, and significantly higher numbers of TIA-1-positive lymphocytes in the latter (P < 0.05). The combined data indicate that expression of PD-L1 by lymphoma cells and TAMs mediate the trafficking of TILs, which may explain the immune-escape process of PCNSLs. In addition, EBV infection appears to affect the trafficking mechanism of TILs, and may thus play an important role in the microenvironment immunity of these tumors.

Reliable diagnosis of IDH-mutant glioblastoma by 2-hydroxyglutarate detection: a study by 3-T magnetic resonance spectroscopy.

We have previously reported that reliable detection of 2-hydroxyglutarate (2HG) in isocitrate dehydrogenase (IDH)-mutant WHO grade 2 and 3 gliomas is possible utilizing 3.0-T single-voxel magnetic resonance spectroscopy (SVMRS). We set out to determine whether the same method could be applied to detect 2HG in IDH-mutant glioblastoma. Forty-four patients harboring glioblastoma underwent pre-operative MRS evaluation to detect 2HG and other metabolites. Presence of IDH-mutations was determined by IDH1 R132H immunohistochemical analysis and DNA sequencing of surgically obtained tissues. Six out of 44 (13.6%) glioblastomas were IDH-mutant. IDH-mutant glioblastoma exhibited significantly higher accumulation of 2HG (median 3.191 vs. 0.000 mM, p < 0.0001, Mann-Whitney test). A cutoff of 2HG = 0.897 mM achieved high sensitivity (100.0%) and specificity (92.59%) in determining IDH-mutation in glioblastoma. Glioblastoma with high 2HG accumulation did not have significantly longer overall survival than glioblastoma with low 2HG accumulation (p = 0.107, log-rank test). Non-invasive and reliable detection of 2HG in IDH-mutant glioblastoma was possible by 3.0-T SVMRS.

Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy.

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aß) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aß deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aß-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aß deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aß deposits in senile plaques. Furthermore, we demonstrated that both Aß40 and Aß42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aß40. Knockdown of SRPX1, in contrast, reduced the formation of Aß40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aß deposits and that may increase Aß-induced cerebrovascular degeneration in CAA.

Long-term survivors of primary central nervous system lymphoma.

Objective: In this study, we provide long-term outcome data of patients with primary central nervous system lymphoma. Methods: The long-term outcomes of PCNSL patients diagnosed between 1982 and 2006 were reviewed. Neurological late neurotoxicity symptoms, neuroradiological brain atrophy and leukoencephalopathy were evaluated. Surviving patients completed the Quality of Life Questionnaire-30 and Brain Cancer Module-20. The differences in overall survival were assessed using the Kaplan-Meier method and log-rank test. The differences between groups in terms of each investigated parameter were analyzed using the Wilcoxon signed-rank test. Results: Among 112 PCNSL patients, there were 33 (29.4%) long-term (> 5 years) survivors. The median survival of all long-term survivors was 105.7 months; of these, 8 (7.1%) were alive at the latest follow-up, with a mean survival time of 170.2 months (range, 121.8­286.4). Clinical assessment revealed severe neurotoxicity in 14 patients (42.4%), moderate neurotoxicity in 5 (15.1%), and normal status in 14 (42.4%). Correlations were seen between the neuroradiological imaging score changes and neurocognitive condition (P=0.0001), neurocognitive condition and the whole brain irradiation dose (P=0.0004), and atrophy and the whole brain irradiation dose (P=0.0035). Conclusions: A more severe clinical condition was found to be associated with increasing age and whole brain irradiation dose in long-term survivors with PCNSL.

Ca2+ -permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma.

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+ -permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+ -permeable AMPA receptors due to dislocation of ADAR2.

GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.

Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.