ABSTRACT
Since the identification of vacuolar protein sorting (VPS) 35, as a causative molecule for familial Parkinson's disease (PD), retromer-mediated endosomal machinery has been a rising factor in the pathogenesis of the disease. The retromer complex cooperates with sorting nexin (SNX) dimer and DNAJC13, another causal molecule in PD, to transport cargoes from endosomes to the trans-Golgi network, and is also involved in mitochondrial dynamics and autophagy. Retromer dysfunction may induce neuronal death leading to PD via several biological cascades, including misfolded, insoluble α-synuclein (aS) accumulation and mitochondrial dysfunction; however, the detailed mechanisms remain poorly understood. In this study, we showed that the stagnation of retromer-mediated retrograde transport consistently occurs in different PD-mimetic conditions, i.e., overexpression of PD-linked mutant DNAJC13, excess aS induction, or toxin-induced mitochondrial dysfunction. Mechanistically, DNAJC13 was found to be involved in clathrin-dependent retromer transport as a functional modulator of SNX1 together with heat shock cognate 70 kDa protein (Hsc70), which was controlled by the binding and dissociation of DNAJC13 and SNX1 in an Hsc70 activity-dependent manner. In addition, excess amount of aS decreased the interaction between SNX1 and VPS35, the core component of retromer. Furthermore, R33, a pharmacological retromer chaperone, reduced insoluble aS and mitigated rotenone-induced neuronal apoptosis. These findings suggest that retrograde transport regulated by SNX1-retromer may be profoundly involved in the pathogenesis of PD and is a potential target for disease-modifying therapy for the disease.
ABSTRACT
BACKGROUND: DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples. OBJECTIVES: To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients. METHODS: A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies. RESULTS: Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups. CONCLUSIONS: Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means.
Subject(s)
Dystonic Disorders , Histone-Lysine N-Methyltransferase , Histones , Mouth Mucosa , Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Dystonic Disorders/genetics , Dystonic Disorders/metabolism , Fibroblasts/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Histones/genetics , Keratinocytes/metabolism , Methylation , Mouth Mucosa/metabolismABSTRACT
Introduction: Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Methods: Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Results: Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. Conclusion: We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.
ABSTRACT
α-Synuclein (αS) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on αS to date have focused on its function in the neuronal cytosol, but its action in the nucleus has also been postulated. Indeed, several lines of evidence indicate that overexpressed αS leads to epigenomic alterations. To clarify the functional role of αS in the nucleus and its pathological significance, HEK293 cells constitutively expressing αS were used to screen for nuclear proteins that interact with αS by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that αS interacts with the BRG1-associated factor (BAF) complex, a family of multi-subunit chromatin remodelers important for neurodevelopment, and protein arginine methyltransferase 5 (PRMT5). Subsequent transcriptomic analysis also suggested a functional link between αS and the BAF complex. Based on these results, we analyzed the effect of αS overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of αS disturbed the BAF maturation process, leading to a global increase in symmetric demethylation of histone H4 on arginine 3 (H4R3me2s) via enhanced BAF-PRMT5 interaction. Chromatin immunoprecipitation sequencing confirmed accumulated H4R3me2s methylation near the transcription start site of the neuronal cell adhesion molecule (NRCAM) gene, which has roles during neuronal differentiation. Transcriptional analyses confirmed the negative regulation of NRCAM by αS and PRMT5, which was reconfirmed by multiple datasets in the Gene Expression Omnibus (GEO) database. Taken together, these findings suggest that the enhanced binding of αS to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.
Subject(s)
Histones , Protein-Arginine N-Methyltransferases , alpha-Synuclein , Humans , Protein-Arginine N-Methyltransferases/metabolism , Protein-Arginine N-Methyltransferases/genetics , Histones/metabolism , Histones/genetics , Methylation , HEK293 Cells , alpha-Synuclein/metabolism , alpha-Synuclein/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , DNA Helicases/metabolism , DNA Helicases/genetics , Arginine/metabolism , Neurons/metabolism , Parkinson Disease/metabolism , Parkinson Disease/genetics , Parkinson Disease/pathologyABSTRACT
Introduction: DYT-KMT2B is a rare childhood-onset, hereditary movement disorder typically characterized by lower-limb dystonia and subsequently spreads into the craniocervical and laryngeal muscles. Recently, KMT2B-encoding lysine (K)-specific histone methyltransferase 2B was identified as the causative gene for DYT-KMT2B, also known as DYT28. In addition to the fact that many physicians do not have sufficient experience or knowledge of hereditary dystonia, the clinical features of DYT-KMT2B overlap with those of other hereditary dystonia, and limited clinical biomarkers make the diagnosis difficult. Methods: Histone proteins were purified from the oral mucosa of patients with de novo KMT2B mutation causing premature stop codon, and then trimethylated fourth lysine residue of histone H3 (H3K4me3) which was catalyzed by KMT2B was analyzed by immunoblotting with specific antibody. We further analyzed the significance of H3K4me3 in patients with DYT-KMT2B using publicly available datasets. Results: H3K4me3 histone mark was markedly lower in the patient than in the control group. Additionally, a reanalysis of publicly available datasets concerning DNA methylation also demonstrated that KMT2B remained inactive in DYT-KMT2B. Discussion: Although only one case was studied due to the rarity of the disease, the reduction of H3K4me3 in the patient's biological sample supports the dysfunction of KMT2B in DYT-KMT2B. Together with informatics approaches, our results suggest that KMT2B haploinsufficiency contributes to the DYT-KMT2B pathogenic process.
ABSTRACT
Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.
Subject(s)
Adaptor Proteins, Vesicular Transport , Parkinson Disease , Synucleinopathies , Animals , Mice , Adaptor Proteins, Vesicular Transport/metabolism , alpha-Synuclein/metabolism , Carrier Proteins , Parkinson Disease/metabolismABSTRACT
Retromer is a highly integrated multimeric protein complex that mediates retrograde cargo sorting from endosomal compartments. In concert with its accessory proteins, the retromer drives packaged cargoes to tubular and vesicular structures, thereby transferring them to the trans-Golgi network or to the plasma membrane. In addition to the endosomal trafficking, the retromer machinery participates in mitochondrial dynamics and autophagic processes and thus contributes to cellular homeostasis. The retromer components and their associated molecules are expressed in different types of cells including neurons and glial cells, and accumulating evidence from genetic and biochemical studies suggests that retromer dysfunction is profoundly involved in the pathogenesis of neurodegenerative diseases including Alzheimer's Disease and Parkinson's disease. Moreover, targeting retromer components could alleviate the neurodegenerative process, suggesting that the retromer complex may serve as a promising therapeutic target. In this review, we will provide the latest insight into the regulatory mechanisms of retromer and discuss how its dysfunction influences the pathological process leading to neurodegeneration.
ABSTRACT
Neurodegenerative diseases are hitherto classified based on their core clinical features, the anatomical distribution of neurodegeneration, and the cell populations mainly affected. On the other hand, the wealth of neuropathological, genetic, molecular and biochemical studies have identified the existence of distinct insoluble protein aggregates in the affected brain regions. These findings have spread the use of a collective term, proteinopathy, for neurodegenerative disorders with particular type of structurally altered protein accumulation. Particularly, a recent breakthrough in this field came with the discovery that these protein aggregates can transfer from one cell to another, thereby converting normal proteins to potentially toxic, misfolded species in a prion-like manner. In this review, we focus specifically on the molecular and cellular basis that underlies the seeding activity and transcellular spreading phenomenon of neurodegeneration-related protein aggregates, and discuss how these events contribute to the disease progression.
Subject(s)
Neurodegenerative Diseases , Prions , Humans , Neurodegenerative Diseases/metabolism , Prions/chemistry , Prions/genetics , Prions/metabolism , Protein Aggregates , Protein FoldingABSTRACT
BACKGROUND Malignant hypertension (MHT), one of the severest forms of hypertension, can have deleterious effects on various organs, such as renal failure, retinopathy, and encephalopathy. These types of organ damage are common complications of MHT, but in several previous cases, damage to other organs, such as the gastrointestinal tract or pancreas, resulting from small vessel lesions, has also been reported, and these cases have had severe clinical outcomes and a poor prognosis. CASE REPORT A 32-year-old male patient with untreated hypertension of a 5-year duration presented with breathlessness and edema. His blood pressure was 220/144 mmHg, and he had renal dysfunction, congestive heart failure, and hypertensive retinopathy. He immediately received treatment, including antihypertensive agents and intermittent hemodialysis, but experienced epigastric pain for several days. A cystic lesion appeared in the pancreatic head, and his serum pancreatic enzymes were elevated. Based on these findings, acute pancreatitis with a cystic lesion was diagnosed. He first received fluid management, pain control, and parenteral nutrition but experienced 2 relapses. Finally, he received transpapillary endoscopic drainage for the cystic lesion with suspected walled-off necrosis. Thereafter, his symptoms improved. CONCLUSIONS The present case of MHT is the first to demonstrate acute necrotizing pancreatitis and it illustrates the difficulty of treatment. Therefore, if a patient with MHT presents with abdominal pain, a thorough workup, including contrast-enhanced computed tomography, should be performed to rule out significant organ involvement.
Subject(s)
Hypertension, Malignant , Pancreatitis, Acute Necrotizing , Acute Disease , Adult , Humans , Hypertension, Malignant/complications , Hypertension, Malignant/therapy , Male , Pancreas , Pancreatitis, Acute Necrotizing/complications , Pancreatitis, Acute Necrotizing/diagnosis , Pancreatitis, Acute Necrotizing/therapyABSTRACT
Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.
ABSTRACT
Membranous nephropathy (MN) with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is seen infrequently. Previous reports of patients with ANCA-GN with MN showed that the most frequent ANCA subtype was myeloperoxidase-ANCA. We herein present a 73-year-old woman with scleritis, hematuria, proteinuria, and positive serum proteinase 3 (PR3)-ANCA. She underwent a renal biopsy and was diagnosed with MN and ANCA-GN. Immunofluorescence staining for PR3 colocalized with IgG along the glomerular basement membrane were observed. Oral prednisolone and intravenous rituximab therapy immediately improved her symptoms and urinalysis abnormalities. PR3-ANCA may be involved in the pathogenesis of MN via the formation of immune complexes.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Glomerulonephritis, Membranous , Glomerulonephritis , Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/complications , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Antibodies, Antineutrophil Cytoplasmic , Female , Glomerulonephritis, Membranous/complications , Glomerulonephritis, Membranous/diagnosis , Glomerulonephritis, Membranous/drug therapy , Humans , Myeloblastin , Peroxidase , Rituximab/therapeutic useABSTRACT
The lateral prefrontal cortex (lPFC) plays a crucial role in the cognitive processes known as executive functions, which are necessary for the planning of goal-directed behavior in complex and constantly changing environments. To adapt to such environments, the lPFC must use its neuronal resources in a flexible manner. To investigate the mechanism by which lPFC neurons code directional information flexibly, the present study explored the tuning properties and time development of lPFC neurons in male Japanese monkeys during a path-planning task, which required them to move a cursor to a final goal in a stepwise manner within a checkerboard-like maze. We identified "axis-tuned" cells that preferred two opposing directions of immediate goals (i.e., vertical and horizontal directions). Among them, a considerable number of these axis-tuned cells dynamically transformed from vector tuning to a single final-goal direction. We also found that the activities of axis-tuned cells, especially pyramidal neurons, were also modulated by the abstract sequence patterns that the animals were to execute. These findings suggest that the axis-tuned cells change what they code (the type of behavioral goal) as well as how they code (their tuning shapes) so that the lPFC can represent a large number of possible actions or sequences with limited neuronal resources. The dynamic axis-tuned cells must reflect the flexible coding of behaviorally relevant information at the single neuron level by the lPFC to adapt to uncertain environments.SIGNIFICANCE STATEMENT The lateral PFC (lPFC) plays a crucial role in the planning of goal-directed behavior in uncertain environments. To adapt to such situations, the lPFC must flexibly encode behaviorally relevant information. Here, we investigated the goal-tuning properties of neuronal firing in the monkey lPFC during a path-planning task. We identified axis-tuned cells that preferred "up-down" or "left-right" immediate goals, and found that many were dynamically transformed from vector tuning to a final-goal direction. The activities of neurons, especially pyramidal neurons, were also modulated by the abstract sequence patterns. Our findings suggest that PFC neurons can alter not only what they code (behavioral goal) but also how they code (tuning shape) when coping with unpredictable environments with limited neuronal resources.
Subject(s)
Executive Function/physiology , Neurons/physiology , Prefrontal Cortex/physiology , Action Potentials/physiology , Animals , Goals , Interneurons/physiology , Macaca fuscata , Male , Microelectrodes , Patch-Clamp Techniques , Prefrontal Cortex/cytology , Psychomotor Performance/physiology , Pyramidal Cells/physiologyABSTRACT
The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1-dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.-Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine/metabolism , Dopaminergic Neurons/pathology , Lewy Bodies/pathology , Membrane Proteins/metabolism , Parkinson Disease/pathology , alpha-Synuclein/metabolism , Aged , Aged, 80 and over , Brain/metabolism , Brain/pathology , Cell Membrane/metabolism , Dopamine Plasma Membrane Transport Proteins/genetics , Dopaminergic Neurons/metabolism , Endocytosis , Humans , Lewy Bodies/metabolism , Membrane Proteins/genetics , Parkinson Disease/genetics , Parkinson Disease/metabolism , Protein Transport , alpha-Synuclein/geneticsABSTRACT
Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human αSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of αSYN, which might predispose to the neurodegenerative process that leads to PD.
Subject(s)
Endosomes/metabolism , Intermediate Filament Proteins/metabolism , Molecular Chaperones/genetics , Mutation , Parkinson Disease/genetics , Actins/metabolism , Animals , Animals, Genetically Modified , Biological Transport , COS Cells , Chlorocebus aethiops , Dopaminergic Neurons/pathology , Drosophila/genetics , Endosomes/genetics , Eye/pathology , Humans , Intermediate Filament Proteins/genetics , Locomotion/genetics , Molecular Chaperones/metabolism , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/genetics , Parkinson Disease/physiopathologyABSTRACT
Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder after Alzheimer's disease. The precise molecular and cellular basis underlying PD still remains uncertain; however, accumulating evidence suggests that neuronal cell death is caused by a combination of environmental and genetic factors. Over the previous two decades, more than 20 genes have been identified as the cause of and/or risk for PD. Because sporadic and familial forms of PD have many similarities in clinical and neuropathological features, common molecular pathways, such as aberrant mitochondrial and protein homeostasis, are likely to exist in both conditions. Of the various genes and proteins involved in PD, the versatile DnaJ/Hsp40 co-chaperones have attracted particular attention since several genes encoding this protein family have been successively identified as the cause of the familial forms of PD/Parkinsonism. In this review, we will introduce the current knowledge regarding the integratory and modulatory effect of DnaJ/Hsp40 in various cellular functions and argue how the failure of these proteins may initiate and/or facilitate of the disease.
ABSTRACT
A 48-year-old woman with a history of autoimmune hemolytic anemia and taking long-term corticosteroid therapy presented with a 3-month history of general fatigue, abdominal distension, and pigmentation. A computed tomography scan of the abdomen showed a tumor in the sigmoid colon and multiple metastatic nodules in the liver. A colonoscopy revealed an obstructing mass with the presence of an irregular ulcer in the sigmoid colon. Following biopsy and histopathological analysis, the patient was diagnosed with neuroendocrine carcinoma (NEC) of the colon. She received her first cycle of chemotherapy, with carboplatin and etoposide. During hospitalization, her pigmentation and hypertension worsened and hypokalemia was observed, all of which suggsted Cushing's syndrome. Her plasma adrenocorticotropic hormone (ACTH) and cortisol levels were high, and an ectopic ACTH-producing tumor was suspected. After a second chemotherapy cycle, she developed neutropenic fever and subsequently died. At autopsy, two histological types were found in the tumor: small cell carcinoma and large cell NEC. Immunohistochemical analysis revealed ACTH in the large cell NEC. This is the first reported case of an ectopic ACTH syndrome caused by NEC of the colon.
Subject(s)
ACTH Syndrome, Ectopic/etiology , Carcinoma, Neuroendocrine/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Sigmoid Neoplasms/diagnostic imaging , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/secondary , Carcinoma, Neuroendocrine/surgery , Combined Modality Therapy , Female , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Middle Aged , Sigmoid Neoplasms/drug therapy , Sigmoid Neoplasms/pathology , Sigmoid Neoplasms/surgery , Tomography, X-Ray ComputedABSTRACT
OBJECTIVE: To determine whether 18F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS). METHODS: We evaluated the in vitro binding of 3H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD). RESULTS: 3H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism. CONCLUSIONS: 18F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.
Subject(s)
Basal Ganglia Diseases/diagnostic imaging , Basal Ganglia Diseases/metabolism , Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Aminopyridines , Autoradiography , Biomarkers/cerebrospinal fluid , Brain Mapping , Diagnosis, Differential , Female , Humans , Male , Mental Status Schedule , Middle Aged , Quinolines , RadiopharmaceuticalsABSTRACT
Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.
Subject(s)
Endoplasmic Reticulum Stress , Endosomal Sorting Complexes Required for Transport/genetics , Endosomal Sorting Complexes Required for Transport/metabolism , Hippocampus/cytology , Phosphoproteins/genetics , Phosphoproteins/metabolism , Prosencephalon/cytology , Animals , Apoptosis , Autophagy , Cell Survival , Gene Silencing , Hippocampus/metabolism , Mice , Necrosis , Prosencephalon/metabolism , Protein Aggregates , Signal Transduction , Ubiquitinated Proteins/metabolismABSTRACT
PURPOSE: To develop an in silico method based on Fick's law of diffusion to estimate the skin concentration following dermal exposure to chemicals with a wide range of lipophilicity. METHODS: Permeation experiments of various chemicals were performed through rat and porcine skin. Permeation parameters, namely, permeability coefficient and partition coefficient, were obtained by the fitting of data to two-layered and one-layered diffusion models for whole and stripped skin. The mean skin concentration of chemicals during steady-state permeation was calculated using the permeation parameters and compared with the observed values. RESULTS: All permeation profiles could be described by the diffusion models. The estimated skin concentrations of chemicals using permeation parameters were close to the observed levels and most data fell within the 95% confidence interval for complete prediction. The permeability coefficient and partition coefficient for stripped skin were almost constant, being independent of the permeant's lipophilicity. CONCLUSIONS: Skin concentration following dermal exposure to various chemicals can be accurately estimated based on Fick's law of diffusion. This method should become a useful tool to assess the efficacy of topically applied drugs and cosmetic ingredients, as well as the risk of chemicals likely to cause skin disorders and diseases.