Publications by authors named "Mei Yue"

51 Publications

The Landscape of Microbial Composition and Associated Factors in Pancreatic Ductal Adenocarcinoma Using RNA-Seq Data.

Front Oncol 2021 31;11:651350. Epub 2021 May 31.

Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.

Recent research studies on interrogation of the tumor microbiome (including bacteria, viruses, and fungi) have yielded important insights into the role of microbes in carcinogenesis, therapeutic responses, and resistance. Once thought to be a sterile organ, a number of studies have showed the presence of microbes within this organ in PDAC status. A microbiome-pancreas axis for PDAC (pancreatic ductal adenocarcinoma) carcinogenesis is proposed. However, the microbial composition of localized PDAC tissue is still unclear. The associations between microbiome and PDAC reported in previous studies were detected in an indirect way, which mostly used samples from stool, oral saliva, and intestinal samples. This study integrated 582 samples derived from PDAC tissues across four datasets and presented a landscape of tumor microbiome at the genus level in PDAC based on remining of RNA-Seq data. On average, there are hundreds of genera distributed in the PDAC tissue, and dozens of core microbiota were identified by PDAC tissue. The pan-microbiome of PDAC tissue was also estimated, which might surpass 2,500 genera. In addition, sampling sites (stroma . epithelium) and tissue source (human tissue . PDX) were found to have great effects on the microbial composition of PDAC tissue, but not the traditional risk factors (sex and age). It is the first study to systematically focus on exploring the microbial composition of PDAC tissue and is helpful to have a deep understanding of tumor microbiome. The identified specific taxa might be potential biomarkers for follow-up research studies.
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http://dx.doi.org/10.3389/fonc.2021.651350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202409PMC
May 2021

Frequency detection of BRAF V600E mutation in a cohort of pediatric langerhans cell histiocytosis patients by next-generation sequencing.

Orphanet J Rare Dis 2021 06 11;16(1):272. Epub 2021 Jun 11.

Department of Hematology, Children's Hospital of Capital Institute of Pediatrics, Beijing, 100020, China.

Background: Langerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients.

Results: We retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence.

Conclusions: This is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.
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http://dx.doi.org/10.1186/s13023-021-01912-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196454PMC
June 2021

Restricted Feeding Resets Endogenous Circadian Rhythm in Female Mice Under Constant Darkness.

Neurosci Bull 2021 Jul 29;37(7):1005-1009. Epub 2021 Mar 29.

Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s12264-021-00669-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275728PMC
July 2021

Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation.

Acta Neuropathol Commun 2020 12 1;8(1):210. Epub 2020 Dec 1.

Department of Neuroscience, Mayo Clinic, Collaborative Research Building CR03-010 13400 E. Shea Blvd, Scottsdale, AZ, 85259, USA.

The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer's disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.
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http://dx.doi.org/10.1186/s40478-020-01079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708249PMC
December 2020

poly(GR) aggregation induces TDP-43 proteinopathy.

Sci Transl Med 2020 09;12(559)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by GC repeat expansions in the gene (c9FTD/ALS). Providing mechanistic insight into the link between mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded GC repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR) mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating GC repeat-expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that GC-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.
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http://dx.doi.org/10.1126/scitranslmed.abb3774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989020PMC
September 2020

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

J Clin Invest 2020 11;130(11):6080-6092

Center for Genomics of Neurodegenerative Disease, and.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
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http://dx.doi.org/10.1172/JCI139741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598060PMC
November 2020

Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo.

Cell Rep 2020 05;31(5):107616

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

A GC hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TGC repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the GC repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.
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http://dx.doi.org/10.1016/j.celrep.2020.107616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480900PMC
May 2020

Application of dispersive liquid-liquid microextraction and GC-MS/MS for the determination of GHB in beverages and hair.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 May 11;1144:122058. Epub 2020 Mar 11.

Department of Forensic Science, Fujian Police College, Fuzhou 350007, PR China; Engineering Research Center, Fujian Police College, Fuzhou 350007, PR China.

Recently, gamma-hydroxybutyrate (GHB) was determined in "Kawa Trendy Drink" which was labeled as a functional beverage containing gamma-aminobutyric acid and quickly became popular in various club in China. GHB has a strong sedative effect and is often used as a date rape drug and euphoriant in drug-facilitated sexual assaults. However, it is believed that same beverages themselves contain natural GHB. Whether GHB contained in seized beverages was added or exists in themselves resulted in complicated interpretation of the nature of cases. The detection window of GHB in blood (5 h) and urine (<12 h) was narrow, make documentation of GHB exposure difficult, while hair can extend the detection time of GHB from several hours to several days/months. Thus, a sensitive detection method based on dispersive liquid-liquid microextraction (DLLME) and GC-MS/MS for GHB in beverages and hair had been established. Under the optimum extraction conditions, acceptable linear relationship was achieved in the range of 1.5-500 ng/mL with the correlation coefficient (r) of 0.9986 for spiked water samples and in the range of 0.03-10 ng/mg with the correlation coefficient (r) of 0.9979 for spiked melanin samples. The LOD (S/N = 3) was estimated to be 0.5 ng/mL and 0.01 ng/mg, respectively. A recovery of 70.6-88.5% were obtained for spiked samples. The mean relative error (MRE) was within ±6.5% and the relative standard error (RSD) was less than 4.9%. The combination of DLLME with GC-MS/MS offers an alternative analytical approach for the sensitive detection of GHB in real beverages sold in Chinese markets and in hair of Chinese population for forensic purposes. The proposed methods had the advantages of shorter extraction time and were suitable for simultaneous pretreatment of samples in batches. To our knowledge, this is the first report to present GHB in beverages and human hair using DLLME.
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http://dx.doi.org/10.1016/j.jchromb.2020.122058DOI Listing
May 2020

Co-expression Network of mRNAs and lncRNAs Regulated by Stress-Linked Behavioral Assays.

Psychopharmacology (Berl) 2020 Feb 23;237(2):571-582. Epub 2019 Nov 23.

Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.

Rationale: Mood-related behavioral assays, designed typically on rodents' natural aversion to certain threats, are useful in studying the mechanisms of mood and in discovering effective treatments for neuropsychiatric disorders.

Objectives: Although reasonable attention has been paid to the conducted sequence, few studies address the argument whether a behavioral assay itself affects the intrinsic signaling, gene expression, and the subsequent performance of mice.

Methods: We examined the short- (1 day) and long-term effects (7 and 14 days) of commonly used behavioral assays for anxiety and depression, including the elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST), on behaviors. We also investigated the effects of repeated behavioral assays on behaviors. The alterations in the expression profiles in the hippocampus experienced behavioral assays were explored via the integrative analysis of mRNA and lncRNA transcriptomes generated by RNA sequencing.

Results: We found that one FST or TST can induce anxiety-related behaviors, while repeated FST or TST resulted in depression-related behaviors in mice. The altered behaviors were associated with extensive transcriptional alterations in the FST and TST hippocampus of mice. KEGG pathway analyses indicated that differentially expressed genes (DEGs) in the FST and TST hippocampus were enriched in anxiety- and metabolic-related pathways, respectively. Moreover, differentially expressed lncRNAs, showing correlations with DEGs, were linked to anxiety-related pathways in the FST hippocampus and metabolic-related pathways in the TST hippocampus.

Conclusions: Our study identified the unique and shared mRNAs and lncRNAs regulated by mood-related behavioral assays, emphasizing the importance of the sequence of and intervals between them.
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http://dx.doi.org/10.1007/s00213-019-05390-1DOI Listing
February 2020

Effects of Dimethyl Phthalate (DMP) on Serum Sex Hormone Levels and Apoptosis in C57 Female Mice.

Int J Endocrinol Metab 2019 Apr 22;17(2):e82882. Epub 2019 Apr 22.

Jilin University School of Public Health, Changchun, China.

Background: The effects of dimethyl phthalate (DMP) on the reproductive system of mammal females are unclear because no studies have been conducted on this topic.

Methods: In this study, 40 C57 female mice were used as experimental subjects and evenly divided into 8 groups, which were fed with mixed DMP (0, 0.5, 1, and 2 g/kg bw/day) and corn oil. After 20 days and 40 days of gavage, the mice were weighed and their individual ovary organ coefficients measured.

Results: Changes were discovered on progesterone, estradiol, follicle-stimulating hormone and luteinizing hormone in mouse serum, and on the apoptosis rate of ovarian granulosa cells.

Conclusions: Prolonged exposure to DMP led to decreased secretion of FSH hormones and increased secretion of E2 and LH hormones. Furthermore, DMP interfered with the pituitary-ovary axis and increased the apoptosis rate of ovarian granulosa cells. Therefore, prolonged exposure to DMP is likely to have negative effects on reproduction and development.
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http://dx.doi.org/10.5812/ijem.82882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628229PMC
April 2019

Gly45 and Phe555 in Transmembrane Domains 1 and 10 Are Critical for the Activation of Organic Anion Transporting Polypeptide 1B3 by Epigallocatechin Gallate.

J Agric Food Chem 2019 Aug 6;67(32):9079-9087. Epub 2019 Aug 6.

Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences , Soochow University , 199 Renai Road , Suzhou Industrial Park, Suzhou , Jiangsu 215123 , People's Republic of China.

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are two highly homologous transporters expressed in the human liver. However, epigallocatechin gallate (EGCG), which is the most predominant catechin in green tea, has opposite effects on the function of OATP1B1 and OATP1B3. In the present study, the critical structural domains and amino acid residues for the activation of OATP1B3 by EGCG have been determined by characterizing the function of a series of OATP1B3-derived chimeric transporters, site-directed mutagenesis, and kinetic studies. Our results showed that G45 and F555 in transmembrane domains 1 and 10 are the most important amino acid residues for OATP1B3 activation. Kinetic studies showed that the activation of OATP1B3 by EGCG at a low substrate concentration was due to its increased substrate binding affinity. However, EGCG caused increased and decreased for 1B3-G45A and 1B3-F555H. The flexibility at position 45 and aromaticity at position 555 might be important for OATP1B3 activation. While 1B3-G45A and 1B3-F555H could not be activated by EGCG, their transport activity for EGCG was comparable to that of wild-type OATP1B3. In conclusion, the present study elucidated the molecular mechanism for OATP1B3 activation by EGCG.
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http://dx.doi.org/10.1021/acs.jafc.9b03812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892160PMC
August 2019

Walnut Shell Powder Can Limit Acid Mine Drainage Formation by Shaping the Bacterial Community Structure.

Curr Microbiol 2019 Oct 5;76(10):1199-1206. Epub 2019 Jul 5.

School of Public Health, Anhui Medical University, Hefei, China.

The formation of acid mine drainage (AMD), which results from the oxidation of sulfur minerals by air and water, can be accelerated by acidophilic and chemolithotrophic bacteria such as Acidithiobacillus ferrooxidans. Our previous study revealed that walnut shell powder and its phenolic component inhibit the growth of A. ferrooxidans. However, their inhibitory effect on AMD formation in the environment needs verification. We established a bioleaching system to test whether walnut shell powder and its phenolic component can limit AMD formation. Our results showed that lignin and cellulose isolated from walnut shell decreased metal ion concentrations through absorption, whereas the phenolic component increased pH by downregulating the expression of Fe-oxidizing genes and rus operon genes of A. ferrooxidans. Only walnut shell powder showed an excellent ability to curb AMD by binding metal ions and increasing the pH value. On probing deeper into the alteration of the bacterial community structure in the bioleaching system, we found that the bacterial community became more diverse-the amount of A. ferrooxidans decreased and that of some non-acidophilic bacteria increased. The bacterial community in samples treated with walnut shell powder or its phenolic component had low abundance in the pathways of metabolism and energy production, as determined by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). In other words, preponderant microbes, mainly A. ferrooxidans, lacked energy to grow well in the treated samples. Our findings provide a practical applicability of walnut shell powder to reduce leaching from a complex environmental community.
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http://dx.doi.org/10.1007/s00284-019-01734-4DOI Listing
October 2019

Heterochromatin anomalies and double-stranded RNA accumulation underlie poly(PR) toxicity.

Science 2019 02;363(6428)

Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, USA.

How hexanucleotide GGGGCC (GC) repeat expansions in cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded GC repeats. The expression of green fluorescent protein-conjugated (PR) (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of -associated FTD and ALS.
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http://dx.doi.org/10.1126/science.aav2606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524780PMC
February 2019

Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant.

Acta Neuropathol Commun 2019 01 23;7(1):10. Epub 2019 Jan 23.

Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, Tau-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in Tau-AAV mice, which were absent the soluble fraction of Tau-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the Tau-AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk.
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http://dx.doi.org/10.1186/s40478-019-0661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345061PMC
January 2019

Altered expressions of memory genes in food-entrained circadian rhythm.

Acta Biochim Biophys Sin (Shanghai) 2018 Oct;50(10):1068-1071

Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.

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http://dx.doi.org/10.1093/abbs/gmy100DOI Listing
October 2018

Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.

Nat Med 2018 08 25;24(8):1136-1142. Epub 2018 Jun 25.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 GC repeat expansion. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR) in the brain. GFP-(GR) mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP-(GR) mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR) mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.
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http://dx.doi.org/10.1038/s41591-018-0071-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520050PMC
August 2018

A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies.

Am J Hum Genet 2018 06 10;102(6):1031-1047. Epub 2018 May 10.

Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. Electronic address:

Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWASs) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is challenging, however, because the functional significance of non-coding mutations is difficult to predict. We propose a statistical framework for analyzing DNMs from whole-genome sequencing (WGS) data. This method, TADA-Annotations (TADA-A), is a major advance of the TADA method we developed earlier for DNM analysis in coding regions. TADA-A is able to incorporate many functional annotations such as conservation and enhancer marks, to learn from data which annotations are informative of pathogenic mutations, and to combine both coding and non-coding mutations at the gene level to detect risk genes. It also supports meta-analysis of multiple DNM studies, while adjusting for study-specific technical effects. We applied TADA-A to WGS data of ∼300 autism-affected family trios across five studies and discovered several autism risk genes. The software is freely available for all research uses.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992125PMC
June 2018

Erratum: Mei, Y., et al. Mechanics Based Tomography: A Preliminary Feasibility Study. Sensors 2017, 17, 1075.

Sensors (Basel) 2018 01 29;18(2). Epub 2018 Jan 29.

Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, USA.

The authors wish to correct Figures 12 and 14 in their paper published in Sensors [1], doi:10.3390/s17051075, http://www.mdpi.com/1424-8220/17/5/1075[...].
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http://dx.doi.org/10.3390/s18020384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855962PMC
January 2018

Evaluation of antitumor activity of survivin short interfering RNA delivered by lipid nanoparticles in colon cancer and .

Oncol Lett 2017 Aug 16;14(2):2001-2008. Epub 2017 Jun 16.

Department of Hematology and Oncology, Capital Institute of Pediatrics, Beijing 100020, P.R. China.

Survivin has been overexpressed in numerous types of cancer and is associated with a poor clinical outcome. A number of various approaches have been used to counteract survivin in order to inhibit tumor growth or promote cell apoptosis. The present study aimed to evaluate the efficiency and antitumor effect of a survivin-targeted short interfering RNA (siRNA) delivery system using lipid nanoparticles for the treatment of colon cancer. Survivin siRNA (si-survivin) nanoliposomes were prepared and transfected into LoVo cells. The mRNA expression level of survivin was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Cell viability was evaluated by MTT assay. LoVo-bearing nude mice were treated with si-survivin intratumorally or intravenously. Tumor growth in LoVo-bearing mice was monitored and recorded, and tumor samples were obtained for evaluation of survivin expression levels using RT-qPCR, western blotting and immunohischemical staining. The expression level of survivin was significantly reduced by nanoliposomal si-survivin along with cell proliferation inhibition . Intravenous administration of si-survivin nanoliposomes may significantly inhibit tumor growth with less toxicity compared with doxorubicin hydrochloride treatment in LoVo-bearing mice. Nanoliposomal si-survivin may significantly reduce the expression level of survivin and inhibit cell proliferation of colon cancer cells and . si-survivin delivered by lipid nanoparticles may be a potential treatment approach for colon cancer.
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http://dx.doi.org/10.3892/ol.2017.6404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530177PMC
August 2017

An acetylation-phosphorylation switch that regulates tau aggregation propensity and function.

J Biol Chem 2017 09 31;292(37):15277-15286. Epub 2017 Jul 31.

From the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224,

The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau's biophysical properties Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6-regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. Because the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer-324 in tau pathobiology and to determine whether therapeutically modulating this acetylation-phosphorylation switch affects disease progression .
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http://dx.doi.org/10.1074/jbc.M117.794602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602388PMC
September 2017

Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways.

Proc Natl Acad Sci U S A 2017 08 12;114(33):E6962-E6971. Epub 2017 Jul 12.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224;

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin () gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood-brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a or background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1; mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1; mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.
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http://dx.doi.org/10.1073/pnas.1701137114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565413PMC
August 2017

Small interfering RNA targeting of the survivin gene inhibits human tumor cell growth .

Exp Ther Med 2017 Jul 23;14(1):35-42. Epub 2017 May 23.

Department of Hematology and Oncology, Capital Institute of Pediatrics, Beijing 100020, P.R. China.

The present study aimed to evaluate the impact of small interfering RNA (siRNA) targeting of the survivin gene in human tumor cells and the effect of decreased survivin expression on the proliferation and apoptosis of tumor cells. Human tumor cell lines (MSA-MB-231, SGC-7901, HeLa, A549, SK-OV-3 and Raji, PC-3) were cultured and divided into three groups: survivin siRNA-treated, scrambled negative control siRNA-treated and an untreated control group. The level of survivin mRNA and protein expression was subsequently determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation was also examined by an MTT assay following transfection and the apoptotic rate of cells was detected by Hoechst and Annexin V/propidium iodide staining. It was observed that relative to the control group, expression of survivin mRNA and protein in the survivin siRNA-treated group was significantly downregulated. Furthermore, siRNA targeting of survivin lead to the inhibition of tumor cell proliferation, as well as an increase in their apoptotic rate . These data suggest that survivin may be a potential tumor biomarker and a novel target for the treatment of cancer.
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http://dx.doi.org/10.3892/etm.2017.4501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488478PMC
July 2017

Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain.

Acta Neuropathol Commun 2017 06 23;5(1):51. Epub 2017 Jun 23.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.

Abnormal accumulation of alpha-synuclein (αsyn) is a pathological hallmark of Lewy body related disorders such as Parkinson's disease and Dementia with Lewy body disease. During the past two decades, a myriad of animal models have been developed to mimic pathological features of synucleinopathies by over-expressing human αsyn. Although different strategies have been used, most models have little or no reliable and predictive phenotype. Novel animal models are a valuable tool for understanding neuronal pathology and to facilitate development of new therapeutics for these diseases. Here, we report the development and characterization of a novel model in which mice rapidly express wild-type αsyn via somatic brain transgenesis mediated by adeno-associated virus (AAV). At 1, 3, and 6 months of age following intracerebroventricular (ICV) injection, mice were subjected to a battery of behavioral tests followed by pathological analyses of the brains. Remarkably, significant levels of αsyn expression are detected throughout the brain as early as 1 month old, including olfactory bulb, hippocampus, thalamic regions and midbrain. Immunostaining with a phospho-αsyn (pS129) specific antibody reveals abundant pS129 expression in specific regions. Also, pathologic αsyn is detected using the disease specific antibody 5G4. However, this model did not recapitulate behavioral phenotypes characteristic of rodent models of synucleinopathies. In fact no deficits in motor function or cognition were observed at 3 or 6 months of age. Taken together, these findings show that transduction of neonatal mouse with AAV-αsyn can successfully lead to rapid, whole brain transduction of wild-type human αsyn, but increased levels of wildtype αsyn do not induce behavior changes at an early time point (6 months), despite pathological changes in several neurons populations as early as 1 month.
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http://dx.doi.org/10.1186/s40478-017-0455-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481919PMC
June 2017

Abcb1a but not Abcg2 played a predominant role in limiting the brain distribution of Huperzine A in mice.

Food Chem Toxicol 2017 Sep 3;107(Pt A):68-73. Epub 2017 Jun 3.

College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Electronic address:

Huperzine A has been used for improving symptoms of Alzheimer's disease. Its cholinergic side effect is thought to be an exaggerated pharmacological outcome linked to its high brain or CNS concentrations. Although Huperzine A is brain penetrable, its interaction with efflux transporters (ABCB1 and ABCG2) has not been fully investigated. The aim of the present study was to characterize roles of ABCB1 and ABCG2 in the transmembrane transport of Huperzine A and identify a rate limiting step in its brain distribution. Data obtained from stably transfected MDCK II cells showed that Huperzine A is a substrate of ABCB1 but not ABCG2. ABCB1 inhibitors significantly inhibited ABCB1 mediated efflux of Huperzine A. In Abcb1a mice, the brain to plasma concentration ratio of Huperzine A was significantly increased as compared to the wild type mice, while there were no obvious differences between the wild type and Abcg2 mice. Taken together, the present study demonstrated that ABCB1 but not ABCG2 played a predominant role in the efflux of Huperzine A across BBB. The current finding is clinically relevant as changes in ABCB1 activity in the presence of ABCB1 inhibitors or genetic polymorphism may affect efficacy and safety of Huperzine A.
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http://dx.doi.org/10.1016/j.fct.2017.06.005DOI Listing
September 2017

Mechanics Based Tomography: A Preliminary Feasibility Study.

Sensors (Basel) 2017 May 9;17(5). Epub 2017 May 9.

Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, USA.

We present a non-destructive approach to sense inclusion objects embedded in a solid medium remotely from force sensors applied to the medium and boundary displacements that could be measured via a digital image correlation system using a set of cameras. We provide a rationale and strategy to uniquely identify the heterogeneous sample composition based on stiffness (here, shear modulus) maps. The feasibility of this inversion scheme is tested with simulated experiments that could have clinical relevance in diagnostic imaging (e.g., tumor detection) or could be applied to engineering materials. No assumptions are made on the shape or stiffness quantity of the inclusions. We observe that the novel inversion method using solely boundary displacements and force measurements performs well in recovering the heterogeneous material/tissue composition that consists of one and two stiff inclusions embedded in a softer background material. Furthermore, the target shear modulus value for the stiffer inclusion region is underestimated and the inclusion size is overestimated when incomplete boundary displacements on some part of the boundary are utilized. For displacements measured on the entire boundary, the shear modulus reconstruction improves significantly. Additionally, we observe that with increasing number of displacement data sets utilized in solving the inverse problem, the quality of the mapped shear moduli improves. We also analyze the sensitivity of the shear modulus maps on the noise level varied between 0.1% and 5% white Gaussian noise in the boundary displacements, force and corresponding displacement indentation. Finally, a sensitivity analysis of the recovered shear moduli to the depth, stiffness and the shape of the stiff inclusion is performed. We conclude that this approach has potential as a novel imaging modality and refer to it as Mechanics Based Tomography (MBT).
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http://dx.doi.org/10.3390/s17051075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470465PMC
May 2017

Survivin downregulation using siRNA nanoliposomes inhibits cell proliferation and promotes the apoptosis of MHCC-97H hepatic cancer cells: An and study.

Oncol Lett 2017 Apr 21;13(4):2723-2730. Epub 2017 Feb 21.

Department of Hematology and Oncology, Capital Institute of Pediatrics, Chaoyang, Beijing 100020, P.R. China.

At present, survivin is one of the most cancer-specific proteins that has been identified. The present study aimed to investigate the antitumor effects of novel survivin small interfering RNA (siRNA) nanoliposomes targeting survivin in human hepatocellular carcinoma MHCC-97H cells and xenograft mouse models. Survivin-targeted siRNA nanoliposomes were prepared and transfected into MHCC-97H cells and MHCC-97H-bearing nude mice. Survivin expression was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell viability was analyzed using an MTT assay and apoptosis was evaluated using Hoechst and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tumor growth in MHCC-97H-bearing mice was monitored following treatment and tumor samples were obtained for survivin expression analysis using RT-qPCR, western blotting and immunohistochemistry staining. Survivin expression levels were significantly downregulated by nanoliposome-mediated survivin siRNA delivery and this was associated with a significant inhibition of cell growth and an increase in the apoptosis of MHCC-97H cells. Downregulation of survivin expression using survivin siRNA nanoliposomes inhibited tumor growth in the MHCC-97H xenograft models without significant treatment-associated toxicity. Therefore, a cationic nanoliposome-based survivin siRNA delivery system was constructed and demonstrated to be efficient for survivin siRNA delivery in and studies. These results demonstrate that survivin downregulation was able to significantly attenuate cell proliferation and induce the apoptosis of MHCC-97H cells, as well as inhibit tumor cell growth in MHCC-97H xenograft models, indicating that survivin suppression using siRNA may contribute to the inhibition of tumor development by suppressing cell proliferation and promoting apoptosis.
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http://dx.doi.org/10.3892/ol.2017.5754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403348PMC
April 2017

Poly(GP) proteins are a useful pharmacodynamic marker for -associated amyotrophic lateral sclerosis.

Sci Transl Med 2017 03;9(383)

Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a GC repeat expansion in the gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. GC repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in -associated ALS (c9ALS). Therapeutics that target GC RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from GC RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target GC RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in GC RNA and downstream GC RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of GC RNA-based therapies in symptomatic repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
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http://dx.doi.org/10.1126/scitranslmed.aai7866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576451PMC
March 2017

Tryptophan Residue Located at the Middle of Putative Transmembrane Domain 11 Is Critical for the Function of Organic Anion Transporting Polypeptide 2B1.

Mol Pharm 2016 10 7;13(10):3553-3563. Epub 2016 Sep 7.

Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, China.

Organic anion transporting polypeptide 2B1 (OATP2B1), which is highly expressed in enterocytes and hepatocytes could be a key determinant for the intestinal absorption and hepatic uptake of its substrates, most of which are amphipathic organic anions. Tryptophan residues may possess a multitude of functions for a transport protein through aromatic interactions, such as maintaining the proper protein structure, guiding the depth of membrane insertion, or interacting directly with substrates. There are totally six tryptophan residues in OATP2B1. However, little is known about their role in the function and expression of OATP2B1. Our results show that, while W272, W276, and W277 located at the border of extracellular loop 3 and transmembrane domain 6 exhibit a moderate effect on the surface expression of OATP2B1, W611 located at the middle of transmembrane domain 11 plays a critical role in the function of OATP2B1. The tryptophan-to-alanine mutation of W611 changes the kinetic characteristics of OATP2B1-mediated estrone-3-sulfate (E3S) transport radically, from a monophasic saturation curve (with K and V values being of 7.1 ± 1.1 μM and 182 ± 7 pmol/normalized mg/min, respectively) to a linear curve. Replacing alanine with a phenylalanine will rescue most of OATP2B1's function, suggesting that the aromatic side chain of residue 611 is very important. However, hydrogen-bond forming and positively charged groups at this position are not favorable. The important role of W611 is not substrate-dependent. Molecular modeling indicates that the side chain of W611 faces toward the substrate translocation pathway and might interact with substrates directly. Taken together, our findings reveal that W611 is critical for the function of OATP2B1.
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http://dx.doi.org/10.1021/acs.molpharmaceut.6b00648DOI Listing
October 2016

Use of Walnut Shell Powder to Inhibit Expression of Fe(2+)-Oxidizing Genes of Acidithiobacillus Ferrooxidans.

Int J Environ Res Public Health 2016 04 30;13(5). Epub 2016 Apr 30.

Department of Biological and Environmental Engineering, Hefei University, Hefei 230601, China.

Acidithiobacillus ferrooxidans is a Gram-negative bacterium that obtains energy by oxidizing Fe(2+) or reduced sulfur compounds. This bacterium contributes to the formation of acid mine drainage (AMD). This study determined whether walnut shell powder inhibits the growth of A. ferrooxidans. First, the effects of walnut shell powder on Fe(2+) oxidization and H⁺ production were evaluated. Second, the chemical constituents of walnut shell were isolated to determine the active ingredient(s). Third, the expression of Fe(2+)-oxidizing genes and rus operon genes was investigated using real-time polymerase chain reaction. Finally, growth curves were plotted, and a bioleaching experiment was performed to confirm the active ingredient(s) in walnut shells. The results indicated that both walnut shell powder and the phenolic fraction exert high inhibitory effects on Fe(2+) oxidation and H⁺ production by A. ferrooxidans cultured in standard 9K medium. The phenolic components exert their inhibitory effects by down-regulating the expression of Fe(2+)-oxidizing genes and rus operon genes, which significantly decreased the growth of A. ferrooxidans. This study revealed walnut shell powder to be a promising substance for controlling AMD.
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http://dx.doi.org/10.3390/ijerph13050461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881086PMC
April 2016

C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins.

Nat Neurosci 2016 05 21;19(5):668-677. Epub 2016 Mar 21.

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
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http://dx.doi.org/10.1038/nn.4272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138863PMC
May 2016
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