Genetics and Genomics Commons^™

Frontotemporal Dementia Nonsense Mutation Of Progranulin Rescued By Aminoglycosides, Lisha Kuang, Kei Hashimoto, Eric J. Huang, Matthew S. Gentry, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Frontotemporal dementia (FTD) is an early onset dementia and is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its function under physiological and pathological conditions remains to be defined. Many FTD-causing nonsense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy.

Aminoglycosides are a class of antibiotics that possess a less known function …

Als Mutations Of Fus Suppress Protein Translation And Disrupt The Regulation Of Nonsense-Mediated Decay, Marisa Kamelgarn, Jing Chen, Lisha Kuang, Huan Jin, Edward J. Kasarskis, Haining Zhu

Toxicology and Cancer Biology Faculty Publications

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed …

Genotype-Phenotype Study In Patients With Valosin-Containing Protein Mutations Associated With Multisystem Proteinopathy, Ebaa Al-Obeidi, Sejad Al-Tahan, Abhilasha Surampalli, Namita Goyal, Annabel K. Wang, Andreas Hermann, Molly Omizo, Charles D. Smith, Tahseen Mozaffar, Virginia Kimonis

Neurology Faculty Publications

Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in …

Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried

Center for Structural Biology Faculty Publications

Human O⁶-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O⁶-alkylguanine and O⁴-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ω_ave. We found …

Zinc Transporters Ybtx And Znuabc Are Required For The Virulence Of Yersinia Pestis In Bubonic And Pneumonic Plague In Mice, Alexander G. Bobrov, Olga Kirillina, Marina Y. Fosso, Jacqueline D. Fetherston, M. Clarke Miller, Tiva T. Vancleave, Joseph A. Burlison, William K. Arnold, Matthew B. Lawrenz, Sylvie Garneau-Tsodikova, Robert D. Perry

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A number of bacterial pathogens require the ZnuABC Zinc (Zn²⁺) transporter and/or a second Zn²⁺ transport system to overcome Zn²⁺ sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn²⁺ transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn²⁺ transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic …

Epigenetic Dominance Of Prion Conformers, Eri Saijo, Hae-Eun Kang, Jifeng Bian, Kristi G. Bowling, Shawn Browning, Sehun Kim, Nora Hunter, Glenn C. Telling

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, …

H2-M3-Restricted Cd8+ T Cells Are Not Required For Mhc Class Ib-Restricted Immunity Against Listeria Monocytogenes, Sarah E. F. D'Orazio, Christine A. Shaw, Michael N. Starnbach

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8⁺ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8⁺ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T …