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JOURNAL ARTICLE
Peter T Nelson, David W Fardo, Xian Wu, Khine Zin Aung, Matthew D Cykowski, Yuriko Katsumata
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains...
April 13, 2024: Journal of Neuropathology and Experimental Neurology
#2
JOURNAL ARTICLE
Vikash Sharma, Jitender Singh, Ashish Kumar, Samarth Kansara, Md Sayeed Akhtar, Mohd Faiyaz Khan, Saad A Aldosari, Monalisa Mukherjee, Arun K Sharma
Identification of concomitant miRNAs and transcription factors (TFs) with differential expression (DEGs) in MI is crucial for understanding holistic gene regulation, identifying key regulators, and precision in biomarker and therapeutic target discovery. We performed a comprehensive analysis using Affymetrix microarray data, advanced bioinformatic tools, and experimental validation to explore potential biomarkers associated with human pathology. The search strategy includes the identification of the GSE83500 dataset, comprising gene expression profiles from aortic wall punch biopsies of MI and non-MI patients, which were used in the present study...
March 27, 2024: European Journal of Pharmacology
#3
JOURNAL ARTICLE
Imogen J Swift, Rosa Rademakers, NiCole Finch, Matt Baker, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Giacomina Rossi, Matthis Synofzik, Carlo Wilke, David Mengel, Caroline Graff, Leonel T Takada, Raquel Sánchez-Valle, Anna Antonell, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Stefanie Schreiber, Stefan Vielhaber, Philipp Arndt, Isabel Santana, Maria Rosario Almeida, Fermín Moreno, Myriam Barandiaran, Alazne Gabilondo, Johannes Stubert, Estrella Gómez-Tortosa, Pablo Agüero, M José Sainz, Tomohito Gohda, Maki Murakoshi, Nozomu Kamei, Sarah Kittel-Schneider, Andreas Reif, Johannes Weigl, Jinlong Jian, Chuanju Liu, Ginette Serrero, Thomas Greither, Gerit Theil, Ebba Lohmann, Stefano Gazzina, Silvia Bagnoli, Giovanni Coppola, Amalia Bruni, Mirja Quante, Wieland Kiess, Andreas Hiemisch, Anne Jurkutat, Matthew S Block, Aaron M Carlson, Geir Bråthen, Sigrid Botne Sando, Gøril Rolfseng Grøntvedt, Camilla Lauridsen, Amanda Heslegrave, Carolin Heller, Emily Abel, Alba Gómez-Núñez, Roger Puey, Andrea Arighi, Enmanuela Rotondo, Lize C Jiskoot, Lieke H H Meeter, João Durães, Marisa Lima, Miguel Tábuas-Pereira, João Lemos, Bradley Boeve, Ronald C Petersen, Dennis W Dickson, Neill R Graff-Radford, Isabelle LeBer, Leila Sellami, Foudil Lamari, Fabienne Clot, Barbara Borroni, Valentina Cantoni, Jasmine Rivolta, Alberto Lleó, Juan Fortea, Daniel Alcolea, Ignacio Illán-Gala, Lucie Andres-Cerezo, Philip Van Damme, Jordi Clarimon, Petra Steinacker, Emily Feneberg, Markus Otto, Emma L van der Ende, John C van Swieten, Harro Seelaar, Henrik Zetterberg, Aitana Sogorb-Esteve, Jonathan D Rohrer
BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations...
March 28, 2024: Alzheimer's Research & Therapy
#4
JOURNAL ARTICLE
Tuancheng Feng, Huan Du, Cha Yang, Ya Wang, Fenghua Hu
TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice...
March 25, 2024: Acta Neuropathologica
#5
JOURNAL ARTICLE
George A Edwards, Caleb A Wood, Yang He, Quynh Nguyen, Peter J Kim, Ruben Gomez-Gutierrez, Kyung-Won Park, Yong Xu, Cody Zurhellen, Ismael Al-Ramahi, Joanna L Jankowsky
TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes...
March 25, 2024: Acta Neuropathologica
#6
JOURNAL ARTICLE
Masashi Fujita, Zongmei Gao, Lu Zeng, Cristin McCabe, Charles C White, Bernard Ng, Gilad Sahar Green, Orit Rozenblatt-Rosen, Devan Phillips, Liat Amir-Zilberstein, Hyo Lee, Richard V Pearse, Atlas Khan, Badri N Vardarajan, Krzysztof Kiryluk, Chun Jimmie Ye, Hans-Ulrich Klein, Gao Wang, Aviv Regev, Naomi Habib, Julie A Schneider, Yanling Wang, Tracy Young-Pearse, Sara Mostafavi, David A Bennett, Vilas Menon, Philip L De Jager
The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level...
March 21, 2024: Nature Genetics
#7
JOURNAL ARTICLE
Yuriko Katsumata, David W Fardo, Lincoln M P Shade, Xian Wu, Shama D Karanth, Timothy J Hohman, Julie A Schneider, David A Bennett, Jose M Farfel, Kathryn Gauthreaux, Charles Mock, Walter A Kukull, Erin L Abner, Peter T Nelson
INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43...
March 9, 2024: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
#8
JOURNAL ARTICLE
Yun-Lu Lin, Tao Yao, Ying-Wei Wang, Zhi-Xiang Zhou, Ze-Chao Hong, Yu Shen, Yu Yan, Yue-Chun Li, Jia-Feng Lin
Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR...
March 1, 2024: Journal of Human Genetics
#9
Jun Yup Lee, Dylan J Harney, Jonathan D Teo, John B Kwok, Greg T Sutherland, Mark Larance, Anthony S Don
No abstract text is available yet for this article.
February 27, 2024: Molecular Neurodegeneration
#10
JOURNAL ARTICLE
Huimin Yan, Minglei Liu, Yuan Gao, Yanpeng Yuan, Xiaojing Liu, Yangyang Wang, Lanjun Li, Qingzhi Wang, Yanlin Wang, Changhe Shi, Yuming Xu, Jing Yang
BACKGROUND: Overwhelming evidence points to that genetic factors contributing to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-Wide Association Study (GWAS) has come a long way in the last decade. So far, a large number of GWAS studies have been published on neurological diseases and many other diseases, providing us with a wealth of genetic information and unique biological insights. METHODS: Genomic DNA was extracted from both patients' and controls' peripheral blood samples utilizing the Blood Genome Extraction Kit...
2024: Frontiers in Neurology
#11
JOURNAL ARTICLE
Kellie Benzow, Kul Karanjeet, Adrian L Oblak, Gregory W Carter, Michael Sasner, Michael D Koob
INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible...
February 11, 2024: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
#12
Yi Zeng, Anastasiia Lovchykova, Tetsuya Akiyama, Chang Liu, Caiwei Guo, Vidhya Maheswari Jawahar, Odilia Sianto, Anna Calliari, Mercedes Prudencio, Dennis W Dickson, Leonard Petrucelli, Aaron D Gitler
In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B ) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.
January 22, 2024: bioRxiv
#13
JOURNAL ARTICLE
Jordan D Marks, Virginia Estades Ayuso, Yari Carlomagno, Mei Yue, Tiffany W Todd, Ying Hao, Ziyi Li, Zachary T McEachin, Anantharaman Shantaraman, Duc M Duong, Lillian M Daughrity, Karen Jansen-West, Wei Shao, Anna Calliari, Jesus Gonzalez Bejarano, Michael DeTure, Bailey Rawlinson, Monica Castanedes Casey, Meredith T Lilley, Megan H Donahue, Vidhya Maheswari Jawahar, Bradley F Boeve, Ronald C Petersen, David S Knopman, Björn Oskarsson, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Keith A Josephs, Yue A Qi, Nicholas T Seyfried, Michael E Ward, Yong-Jie Zhang, Mercedes Prudencio, Leonard Petrucelli, Casey N Cook
Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation...
January 17, 2024: Science Translational Medicine
#14
JOURNAL ARTICLE
Xiaoyu Zhao, Feng Gao
The recent discovery that TMEM106B serves as a receptor mediating ACE2-independent SARS-CoV-2 entry into cells deserves attention, especially in the background of the frequent emergence of mutant strains. Here, the structure-dynamic features of this novel pathway are dissected deeply. Our investigation revealed that the large loop (RBD@471-491) could anchor TMEM106B, which was then firmly locked by another loop (RBD@444-451). The novel and widely disseminated Omicron variants (BA.2.86/EG.5.1) affect the anchoring recognition of proteins, with BA...
January 11, 2024: Journal of Physical Chemistry Letters
#15
JOURNAL ARTICLE
Keith A Josephs, Shunsuke Koga, Nirubol Tosakulwong, Stephen D Weigand, Trang Thu Nha Pham, Matt Baker, Jennifer L Whitwell, Rosa Rademakers, Leonard Petrucelli, Dennis W Dickson
TAR DNA binding protein 43 (TDP-43) pathology is a defining feature of frontotemporal lobar degeneration (FTLD). In FTLD-TDP there is a moderate-to-high burden of morphologically distinctive TDP-43 immunoreactive inclusions distributed throughout the brain. In Alzheimer's disease (AD), similar TDP-43 immunoreactive inclusions are observed. In AD, however, there is a unique phenomenon of neurofibrillary tangle-associated TDP-43 (TATs) whereby TDP-43 intermingles with neurofibrillary tangles. Little is known about the characteristics and distribution of TATs, or how burden and distribution of TATs compares to burden and distribution of other FTLD-TDP-like lesions observed in AD...
January 2023: Free neuropathology
#16
Tuancheng Feng, Huan Du, Fenghua Hu
TMEM106B , a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice...
November 15, 2023: bioRxiv
#17
JOURNAL ARTICLE
Indranil Basak, Rhodri Harfoot, Jennifer E Palmer, Abhishek Kumar, Miguel E Quiñones-Mateu, Lucia Schweitzer, Stephanie M Hughes
Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection...
October 30, 2023: Biomolecules
#18
JOURNAL ARTICLE
Sara L Dominguez, Benjamin I Laufer, Arundhati Sengupta Ghosh, Qingling Li, Gaia Ruggeri, Maheswara Reddy Emani, Lilian Phu, Brad A Friedman, Wendy Sandoval, Christopher M Rose, Hai Ngu, Oded Foreman, Mike Reichelt, Yves Juste, Guita Lalehzadeh, Dennis Hansen, Helle Nymark, Denia Mellal, Helene Gylling, Łukasz J Kiełpiński, Ben Chih, Baris Bingol, Casper C Hoogenraad, William J Meilandt, Amy Easton
Heterozygous mutations in the granulin ( GRN ) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency...
November 17, 2023: IScience
#19
JOURNAL ARTICLE
Ruoyi Ishikawa, Yu Yamazaki, Masahiro Nakamori, Tetsuya Takahashi, Hirofumi Maruyama
Accumulation of TMEM106B fibrils composed of cleaved C-terminal fragments (CTF) of transmembrane protein 106B (TMEM106B) has recently been observed in the brains of elderly subjects and individuals with neurodegenerative diseases. To date, one antibody recognizing the residues 239-250 has been found to display immunoreactivity to the TMEM106B CTF, thereby defining TMEM106B C-terminal immunoreactive (TMEM-ir) material. Immunohistochemical characterization of the CTF using antibodies targeting different immunogens could further shed light on the attributes of TMEM-ir material and the biological relevance of TMEM106B fibril accumulation in vivo ...
2023: Frontiers in Neuroscience
#20
JOURNAL ARTICLE
Quynh Nguyen, Caleb A Wood, Peter J Kim, Joanna L Jankowsky
The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer's disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with resilience. Only one coding polymorphism distinguishes the two alleles, a threonine-to-serine substitution at residue 185 (186 in mouse), that is inherited in disequilibrium with multiple non-coding variants. Transcriptional studies suggest synaptic, neuronal, and cognitive preservation in human subjects with the protective haplotype, while murine in vitro studies reveal dramatic effects of TMEM106B deletion on neuronal development...
2023: Frontiers in Neuroscience
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