Proteasomal dysfunction is known to be associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). Our previous reports have shown that a mutant form of ubiquilin-2 ...(UBQLN2) linked to ALS/FTD leads to neurodegeneration accompanied by accumulations of the proteasome subunit Rpt1 in transgenic rats, but the precise pathogenic mechanisms of how this mutation impairs the proteasome remains to be elucidated. Here, we reveal that this UBQLN2 mutation in rats disrupted the proteasome integrity prior to neurodegeneration, that it dissociated the 26S proteasome in vitro, and that its depletion did not affect 26S proteasome assembly. During both disease progression and in an age-dependent manner, we found that proteasome subunits were translocated to the nucleus, including both of the 20S core particles (PSMA1 and PSMB7) and the 19S regulatory particles (Rpt1 and Rpn1), suggesting that defective proteasome function may result from the proteasome-subunit mislocalization. Taken together, the present data demonstrate that impaired proteasome assembly is an early event in the pathogenesis of UBQLN2-associated neurodegeneration in mutant UBQLN2 rats.
Mutation of Tar DNA‐binding protein 43 (TDP‐43) is linked to amyotrophic lateral sclerosis. Although astrocytes have important roles in neuron function and survival, their potential contribution to ...TDP‐43 pathogenesis is unclear. Here, we created novel lines of transgenic rats that express a mutant form of human TDP‐43 (M337V substitution) restricted to astrocytes. Selective expression of mutant TDP‐43 in astrocytes caused a progressive loss of motor neurons and the denervation atrophy of skeletal muscles, resulting in progressive paralysis. The spinal cord of transgenic rats also exhibited a progressive depletion of the astroglial glutamate transporters GLT‐1 and GLAST. Astrocytic expression of mutant TDP‐43 led to activation of astrocytes and microglia, with an induction of the neurotoxic factor Lcn2 in reactive astrocytes that was independent of TDP‐43 expression. These results indicate that mutant TDP‐43 in astrocytes is sufficient to cause non‐cell‐autonomous death of motor neurons. This motor neuron death likely involves deficiency in neuroprotective genes and induction of neurotoxic genes in astrocytes.
The debated role of astrocytes in amyotrophic lateral sclerosis (ALS) gains additional support from neurodegenerative phenotypes caused by astrocyte‐restricted expression of mutant TDP‐43 in transgenic rats.
In this work, we present a catalog of 2651 carbon stars from the fourth Data Release (DR4) of the Large Sky Area Multi-Object Fiber Spectroscopy Telescope (LAMOST). Using an efficient ...machine-learning algorithm, we find these stars from more than 7 million spectra. As a by-product, 17 carbon-enhanced metal-poor turnoff star candidates are also reported in this paper, and they are preliminarily identified by their atmospheric parameters. Except for 176 stars that could not be given spectral types, we classify the other 2475 carbon stars into five subtypes: 864 C-H, 226 C-R, 400 C-J, 266 C-N, and 719 barium stars based on a series of spectral features. Furthermore, we divide the C-J stars into three subtypes, C-J(H), C-J(R), and C-J(N), and about 90% of them are cool N-type stars as expected from previous literature. Besides spectroscopic classification, we also match these carbon stars to multiple broadband photometries. Using ultraviolet photometry data, we find that 25 carbon stars have FUV detections and that they are likely to be in binary systems with compact white dwarf companions.
Pathogenic mutation of ubiquilin 2 (UBQLN2) causes neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. How UBQLN2 mutations cause the diseases is not clear. ...While over‐expression of UBQLN2 with pathogenic mutation causes neuron death in rodent models, deletion of the Ubqln2 in rats has no effect on neuronal function. Previous findings in animal models suggest that UBQLN2 mutations cause the diseases mainly through a gain rather than a loss of functions. To examine whether the toxic gain in UBQLN2 mutation is related to the enhancement of UBQLN2 functions, we created new transgenic rats over‐expressing wild‐type human UBQLN2. Considering that human UBQLN2 may not function properly in the rat genome, we also created transgenic rats over‐expressing rat's own Ubqln2. When over‐expressed in rats, both human and rat wild‐type Ubqln2 caused neuronal death and spatial learning deficits, the pathologies that were indistinguishable from those observed in mutant UBQLN2 transgenic rats. Over‐expressed wild‐type UBQLN2 formed protein inclusions attracting the autophagy substrate sequestosome‐1 and the proteasome component 26S proteasome regulatory subunit 7. These findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that the enhancement of UBQLN2 functions is involved in UBQLN2 pathogenesis.
Pathogenic mutation in ubiquilin 2 (UBQLN2) causes neurodegeneration in ALS and FTLD. Studies in rodent models suggest a gain of toxic function in mutant UBQLN2. We created new transgenic rats as a relevant model and examined whether enhancing wild‐type UBQLN2 expression is implicated in the pathogenesis of mutant UBQLN2. We observed that over‐expression of human or rat wild‐type Ubqln2 caused protein aggregation and neuronal death in transgenic rats. Our findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that uncontrolled enhancement of UBQLN2 function is involved in UBQLN2 pathogenesis.
Read the Editorial Highlight for this article on page 159.
Pathogenic mutation in ubiquilin 2 (UBQLN2) causes neurodegeneration in ALS and FTLD. Studies in rodent models suggest a gain of toxic function in mutant UBQLN2. We created new transgenic rats as a relevant model and examined whether enhancing wild‐type UBQLN2 expression is implicated in the pathogenesis of mutant UBQLN2. We observed that over‐expression of human or rat wild‐type Ubqln2 caused protein aggregation and neuronal death in transgenic rats. Our findings suggest that excess UBQLN2 is toxic rather than protective to neurons and that uncontrolled enhancement of UBQLN2 function is involved in UBQLN2 pathogenesis.
Read the Editorial Highlight for this article on page 159.
Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms ...have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.
A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate ...the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation.
The relationship between headache and thyrotoxicosis has been occasionally mentioned in case reports, but there are few related reports. Thus, the relationship cannot be determined. Few cases of ...subacute thyroiditis (SAT) presenting as simple headache have been reported.
This case report describes a middle-aged male patient who came to our hospital with acute headache for 10 days. He was initially misdiagnosed as meningitis due to headache, fever, and increased C-reactive protein. Routine antibacterial and antiviral therapy did not improve his symptoms. Blood test suggested thyrotoxicosis, and color ultrasound suggested SAT sonography. He was diagnosed with SAT. With the treatment of SAT, the headache was relieved after the thyrotoxicosis improved.
This patient is the first detailed report of SAT presenting with simple headache, which is helpful for clinicians to differentiate and diagnose atypical SAT.
ObjectiveThis study aims to investigate physicians’ familiarity and awareness of four diabetes guidelines and their practice of the recommendations outlined in these guidelines.DesignA ...cross-sectional study.SettingAn online questionnaire survey was conducted among physicians affiliated with the Specialist Committee for Primary Diabetes Care of China Association of Chinese Medicine, using the snowball sampling method to ensure a broader representation of physicians.Participants1150 physicians from 192 cities across 30 provinces in China provided complete data.ResultsTertiary care hospital physicians (TCPs) exhibited the highest familiarity with the Guideline for the Prevention and Treatment of Type 2 Diabetes Mellitus in China (91.3%), followed by the National Guidelines for the Prevention and Control of Diabetes in Primary Care (76.8%), the Standards of Medical Care in Diabetes (72.2%) and the Guidelines for Prevention and Treatment of Diabetes in Chinese Medicine (63.8%). Primary care practitioners (PCPs) exhibited familiarity with these four guidelines at about 50% or less. Self-reported reference to modern diabetes guidelines by physicians is more frequent than traditional Chinese medicine (TCM) diabetes guidelines, with rates at 73.2% and 33.8%, respectively. Approximately 90% of physicians provided instructions on self-monitoring of blood glucose to their patients with diabetes. Less than one-third of physicians referred patients to a specialised nutritionist. In terms of health education management, TCPs reported having a diabetes health management team at the rate of 75.7%, followed by secondary care hospital physicians at 57.0% and PCPs at 27.5%. Furthermore, approximately 40% of physicians did not fully grasp hypoglycaemia characteristics.ConclusionsFamiliarity and awareness of the screening guidelines varied among physicians in different hospital settings. Importantly, significant discrepancies were observed between physicians’ awareness and their self-reported reference to modern medicine guidelines and TCM guidelines. It is essential to consistently provide education and training on diabetes management for all physicians, particularly PCPs.
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