Real-time imaging of Huntingtin aggregates diverting target search and gene transcription. 2016

Li Li, and Hui Liu, and Peng Dong, and Dong Li, and Wesley R Legant, and Jonathan B Grimm, and Luke D Lavis, and Eric Betzig, and Robert Tjian, and Zhe Liu
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.

The presumptive altered dynamics of transient molecular interactions in vivo contributing to neurodegenerative diseases have remained elusive. Here, using single-molecule localization microscopy, we show that disease-inducing Huntingtin (mHtt) protein fragments display three distinct dynamic states in living cells - 1) fast diffusion, 2) dynamic clustering and 3) stable aggregation. Large, stable aggregates of mHtt exclude chromatin and form 'sticky' decoy traps that impede target search processes of key regulators involved in neurological disorders. Functional domain mapping based on super-resolution imaging reveals an unexpected role of aromatic amino acids in promoting protein-mHtt aggregate interactions. Genome-wide expression analysis and numerical simulation experiments suggest mHtt aggregates reduce transcription factor target site sampling frequency and impair critical gene expression programs in striatal neurons. Together, our results provide insights into how mHtt dynamically forms aggregates and disrupts the finely-balanced gene control mechanisms in neuronal cells.

UI MeSH Term Description Entries
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D000066450 Mouse Embryonic Stem Cells PLURIPOTENT STEM CELLS derived from the BLASTOCYST INNER CELL MASS of day 3.5 mouse embryos. mESC,Cells, Mouse Embryonic Stem,Mouse Embryonic Stem Cell,Stem Cells, Mouse Embryonic,mESCs
D000071058 Huntingtin Protein A protein that is highly expressed in the nervous system as well as other tissues; its size and structure vary due to polymorphisms. Expanded CAG TRINUCLEOTIDE REPEATS have been identified in the Huntingtin (HD) Gene of patients with HUNTINGTON DISEASE and are associated with abnormal PROTEIN AGGREGATES. Huntingtin interacts with proteins involved in a variety of gene expression and cellular processes; it is also essential for embryonic development. Huntington Disease Protein,IT15 Protein
D000072760 Single Molecule Imaging High resolution imaging techniques that allow visualization of individual molecules of proteins, lipids, or nucleic acids within cells or tissues. Single Molecule Analysis,Single Molecule Tracking,Single Particle Analysis,Single Particle Imaging,Single Particle Microscopy,Single Particle Spectroscopy,Single Particle Tracking,Single Molecule Microscopy,Single Molecule Spectroscopy,Analyses, Single Particle,Analysis, Single Molecule,Analysis, Single Particle,Imaging, Single Molecule,Imaging, Single Particle,Microscopies, Single Particle,Microscopy, Single Molecule,Microscopy, Single Particle,Particle Tracking, Single,Single Molecule Analyses,Single Particle Analyses,Single Particle Microscopies,Single Particle Spectroscopies,Single Particle Trackings,Spectroscopy, Single Molecule,Spectroscopy, Single Particle,Tracking, Single Molecule,Tracking, Single Particle
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D014158 Transcription, Genetic The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION. Genetic Transcription
D014793 Visual Cortex Area of the OCCIPITAL LOBE concerned with the processing of visual information relayed via VISUAL PATHWAYS. Area V2,Area V3,Area V4,Area V5,Associative Visual Cortex,Brodmann Area 18,Brodmann Area 19,Brodmann's Area 18,Brodmann's Area 19,Cortical Area V2,Cortical Area V3,Cortical Area V4,Cortical Area V5,Secondary Visual Cortex,Visual Cortex Secondary,Visual Cortex V2,Visual Cortex V3,Visual Cortex V3, V4, V5,Visual Cortex V4,Visual Cortex V5,Visual Cortex, Associative,Visual Motion Area,Extrastriate Cortex,Area 18, Brodmann,Area 18, Brodmann's,Area 19, Brodmann,Area 19, Brodmann's,Area V2, Cortical,Area V3, Cortical,Area V4, Cortical,Area V5, Cortical,Area, Visual Motion,Associative Visual Cortices,Brodmanns Area 18,Brodmanns Area 19,Cortex Secondary, Visual,Cortex V2, Visual,Cortex V3, Visual,Cortex, Associative Visual,Cortex, Extrastriate,Cortex, Secondary Visual,Cortex, Visual,Cortical Area V3s,Extrastriate Cortices,Secondary Visual Cortices,V3, Cortical Area,V3, Visual Cortex,V4, Area,V4, Cortical Area,V5, Area,V5, Cortical Area,V5, Visual Cortex,Visual Cortex Secondaries,Visual Cortex, Secondary,Visual Motion Areas
D050505 Mutant Proteins Proteins produced from GENES that have acquired MUTATIONS. Mutant Protein,Protein, Mutant,Proteins, Mutant

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