Time-resolved FRET screening identifies small molecular modifiers of mutant Huntingtin conformational inflexibility in patient-derived cells

Pringsheim, 2012, The Incidence and Prevalence of Huntington's Disease: A Systematic Review and Meta-Analysis, Mov Disord, 27, 1083, 10.1002/mds.25075 McColgan, 2018, Huntington's Disease: A Clinical Review, Eur J Neurol, 25, 24, 10.1111/ene.13413 Imarisio, 2008, Huntington's Disease: From Pathology and Genetics to Potential Therapies, Biochem J, 412, 191, 10.1042/BJ20071619 Kaltenbach, 2007, Huntingtin Interacting Proteins Are Genetic Modifiers of Neurodegeneration, PLOS Genet, 3, e82, 10.1371/journal.pgen.0030082 Li, 2004, Huntingtin-Protein Interactions and the Pathogenesis of Huntington's Disease, Trends Genet. TIG, 20, 146, 10.1016/j.tig.2004.01.008 Li, 2019, Allele-Selective Lowering of Mutant HTT Protein by HTT–LC3 Linker Compounds, Nature, 575, 203, 10.1038/s41586-019-1722-1 Tabrizi, 2019, Targeting Huntingtin Expression in Patients with Huntington's Disease, N Engl J Med, 380, 2307, 10.1056/NEJMoa1900907 Auerbach, 2001, The HD Mutation Causes Progressive Lethal Neurological Disease in Mice Expressing Reduced Levels of Huntingtin, Hum Mol Genet, 10, 2515, 10.1093/hmg/10.22.2515 Saudou, 2016, The Biology of Huntingtin, Neuron, 89, 910, 10.1016/j.neuron.2016.02.003 Wang, 2016, Ablation of Huntingtin in Adult Neurons Is Nondeleterious but Its Depletion in Young Mice Causes Acute Pancreatitis, Proc Natl Acad Sci U S A, 113, 3359, 10.1073/pnas.1524575113 Molero, 2016, Selective Expression of Mutant Huntingtin during Development Recapitulates Characteristic Features of Huntington's Disease, Proc Natl Acad Sci, 113, 5736, 10.1073/pnas.1603871113 Yang, 2020, Truncation of Mutant Huntingtin in Knock-in Mice Demonstrates Exon1 Huntingtin Is a Key Pathogenic Form, Nat Commun, 11, 2582, 10.1038/s41467-020-16318-1 Burrus, 2020, Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival, Cell Rep, 30, 642, 10.1016/j.celrep.2019.12.069 Jung, 2021, Mutations Causing Lopes-Maciel-Rodan Syndrome Are Huntingtin Hypomorphs, Hum Mol Genet, 10.1093/hmg/ddaa283 Caron, 2013, Polyglutamine Domain Flexibility Mediates the Proximity between Flanking Sequences in Huntingtin, Proc Natl Acad Sci U S A, 110, 14610, 10.1073/pnas.1301342110 Kang, 2017, Emerging β-Sheet Rich Conformations in Super-Compact Huntingtin Exon-1 Mutant Structures, J Am Chem Soc, 139, 8820, 10.1021/jacs.7b00838 Bravo-Arredondo, 2018, The Folding Equilibrium of Huntingtin Exon 1 Monomer Depends on Its Polyglutamine Tract, J Biol Chem, 293, 19613, 10.1074/jbc.RA118.004808 Daldin, 2017, Polyglutamine Expansion Affects Huntingtin Conformation in Multiple Huntington's Disease Models, Sci Rep, 7, 5070, 10.1038/s41598-017-05336-7 Fodale, 2014, Polyglutamine- and Temperature-Dependent Conformational Rigidity in Mutant Huntingtin Revealed by Immunoassays and Circular Dichroism Spectroscopy, PLoS One, 9, 10.1371/journal.pone.0112262 Cui, 2014, TR-FRET Assays of Huntingtin Protein Fragments Reveal Temperature and PolyQ Length-Dependent Conformational Changes, Sci Rep, 4, 1, 10.1038/srep05601 Williamson, 2010, Modulation of Polyglutamine Conformations and Dimer Formation by the N-Terminus of Huntingtin, J Mol Biol, 396, 1295, 10.1016/j.jmb.2009.12.017 Vieweg, 2021, Towards Deciphering the Nt17 Code: How the Sequence and Conformation of the First 17 Amino Acids in Huntingtin Regulate the Aggregation, Cellular Properties and Neurotoxicity of Mutant Httex1, bioRxiv Gu, 2009, Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD Mice, Neuron, 64, 828, 10.1016/j.neuron.2009.11.020 Arbez, 2017, Post-Translational Modifications Clustering within Proteolytic Domains Decrease Mutant Huntingtin Toxicity, J Biol Chem, 292, 19238, 10.1074/jbc.M117.782300 Cariulo, 2017, Phosphorylation of Huntingtin at Residue T3 Is Decreased in Huntington's Disease and Modulates Mutant Huntingtin Protein Conformation, Proc Natl Acad Sci, 114, E10809, 10.1073/pnas.1705372114 DeGuire, 2018, N-Terminal Huntingtin (Htt) Phosphorylation Is a Molecular Switch Regulating Htt Aggregation, Helical Conformation, Internalization, and Nuclear Targeting, J Biol Chem, 293, 18540, 10.1074/jbc.RA118.004621 Pardo, 2012, Ganglioside GM1 Induces Phosphorylation of Mutant Huntingtin and Restores Normal Motor Behavior in Huntington Disease Mice, Proc Natl Acad Sci, 109, 3528, 10.1073/pnas.1114502109 Atwal, 2011, Kinase Inhibitors Modulate Huntingtin Cell Localization and Toxicity, Nat Chem Biol, 7, 453, 10.1038/nchembio.582 Bowie, 2018, N6-Furfuryladenine Is Protective in Huntington's Disease Models by Signaling Huntingtin Phosphorylation, Proc Natl Acad Sci, 115, E7081, 10.1073/pnas.1801772115 Lee, 2019, CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset, Cell, 178, 887, 10.1016/j.cell.2019.06.036 Caron, 1993, Huntington Disease Wexler, 2004, Venezuelan Kindreds Reveal That Genetic and Environmental Factors Modulate Huntington's Disease Age of Onset, Proc Natl Acad Sci U S A, 101, 3498, 10.1073/pnas.0308679101 Claassen, 2020, Genotyping Single Nucleotide Polymorphisms for Allele-Selective Therapy in Huntington Disease, Neurol Genet, 6, e430, 10.1212/NXG.0000000000000430 Mongelli, 2020, Frequency and Distribution of PolyQ Disease Intermediate-Length Repeat Alleles in Healthy Italian Population, Neurol Sci, 41, 1475, 10.1007/s10072-019-04233-3 Ko, 2001, New Anti-Huntingtin Monoclonal Antibodies: Implications for Huntingtin Conformation and Its Binding Proteins, Brain Res Bull, 56, 319, 10.1016/S0361-9230(01)00599-8 Schindelin, 2012, Fiji: An Open-Source Platform for Biological-Image Analysis, Nat Methods, 9, 676, 10.1038/nmeth.2019 Berthold, 2008, KNIME: The Konstanz Information Miner, 319, 10.1007/978-3-540-78246-9_38 Waskom, 2020, 11, 2020 Zheng, 2013, An N-Terminal Nuclear Export Signal Regulates Trafficking and Aggregation of Huntingtin (Htt) Protein Exon 1, J Biol Chem, 288, 6063, 10.1074/jbc.M112.413575 Thompson, 2009, IKK Phosphorylates Huntingtin and Targets It for Degradation by the Proteasome and Lysosome, J Cell Biol, 187, 1083, 10.1083/jcb.200909067 Mishra, 2012, Serine Phosphorylation Suppresses Huntingtin Amyloid Accumulation by Altering Protein Aggregation Properties, J Mol Biol, 424, 1, 10.1016/j.jmb.2012.09.011 Bray, 2004, Imaging Platform, Broad Institute of MIT and Harvard. Advanced Assay Development Guidelines for Image-Based High Content Screening and Analysis Yalinca, 2019, The Role of Post-Translational Modifications on the Energy Landscape of Huntingtin N-Terminus, Front Mol Biosci, 6, 95, 10.3389/fmolb.2019.00095 Chiki, 2017, Mutant Exon1 Huntingtin Aggregation Is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6, Angew Chem Int Ed Engl, 56, 5202, 10.1002/anie.201611750 DeGuire, 2018, N-Terminal Huntingtin (Htt) Phosphorylation Is a Molecular Switch Regulating Htt Aggregation, Helical Conformation, Internalization, and Nuclear Targeting, J Biol Chem, 293, 18540, 10.1074/jbc.RA118.004621 Bonfanti, 2019, Molecular Mechanisms of Heterogeneous Oligomerization of Huntingtin Proteins, Sci Rep, 9, 7615, 10.1038/s41598-019-44151-0 Branco-Santos, 2017, Protein Phosphatase 1 Regulates Huntingtin Exon 1 Aggregation and Toxicity, Hum Mol Genet, 26, 3763, 10.1093/hmg/ddx260 Chaibva, 2016, Acetylation within the First 17 Residues of Huntingtin Exon 1 Alters Aggregation and Lipid Binding, Biophys J, 111, 349, 10.1016/j.bpj.2016.06.018 Chiki, 2017, Mutant Exon1 Huntingtin Aggregation Is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6, Angew Chem, Int Ed, 56, 5202, 10.1002/anie.201611750 Watkin, 2014, Phosphorylation of Mutant Huntingtin at Serine 116 Modulates Neuronal Toxicity, PLoS One, 9, e88284, 10.1371/journal.pone.0088284 Luo, 2005, Cdk5 Phosphorylation of Huntingtin Reduces Its Cleavage by Caspases, J Cell Biol, 169, 647, 10.1083/jcb.200412071 Schilling, 2006, Huntingtin Phosphorylation Sites Mapped by Mass Spectrometry. Modulation of Cleavage and Toxicity, J Biol Chem, 281, 23686, 10.1074/jbc.M513507200 Baldo, 2012, TR-FRET-Based Duplex Immunoassay Reveals an Inverse Correlation of Soluble and Aggregated Mutant Huntingtin in Huntington's Disease, Chem Biol, 19, 264, 10.1016/j.chembiol.2011.12.020 Reindl, 2019, Meso Scale Discovery-Based Assays for the Detection of Aggregated Huntingtin, PLoS One, 14, 10.1371/journal.pone.0213521 McMurray, 2010, Mechanisms of Trinucleotide Repeat Instability during Human Development, Nat Rev Genet, 11, 786, 10.1038/nrg2828 Truant, 2006, Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases, Can J Neurol Sci, 33, 278, 10.1017/S031716710000514X Ehrnhoefer, 2011, Big Impact: Posttranslational Modifications and Function of Huntingtin in Huntington Disease, Neurosci Rev J Bringing Neurobiol Neurol Psychiatry, 17, 475 Nguyen, 2013, Cerebellar Soluble Mutant Ataxin-3 Level Decreases during Disease Progression in Spinocerebellar Ataxia Type 3 Mice, PLoS One, 8, e62043, 10.1371/journal.pone.0062043 Wilke, 2020, Neurofilaments in Spinocerebellar Ataxia Type 3: Blood Biomarkers at the Preataxic and Ataxic Stage in Humans and Mice, EMBO Mol Med, 12, e11803, 10.15252/emmm.201911803 Gonsior, 2020, PolyQ-Expanded Ataxin-3 Protein Levels in Peripheral Blood Mononuclear Cells Correlate with Clinical Parameters in SCA3: A Pilot Study, J Neurol, 268, 1304, 10.1007/s00415-020-10274-y