Abstract
Many genetic mouse models of Huntington's disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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Behavior, Animal
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Blotting, Western
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Brain / metabolism
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Brain / pathology*
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Chromatography, Liquid
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Dopamine / metabolism
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Exons / genetics
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Female
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Fluorescent Antibody Technique
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Glutamic Acid / metabolism
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Humans
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Huntingtin Protein
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Huntington Disease / etiology*
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Huntington Disease / metabolism
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Huntington Disease / pathology
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Immunoenzyme Techniques
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Immunoprecipitation
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Male
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Mice
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Mice, Transgenic
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Mutation / genetics*
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Nerve Tissue Proteins / physiology*
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Neurons / metabolism
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Neurons / pathology
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Peptides / genetics
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Phosphorylation
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Presynaptic Terminals / metabolism
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Presynaptic Terminals / pathology*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Synapsins / genetics
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Synapsins / metabolism*
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Synaptic Transmission
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Synaptosomal-Associated Protein 25 / genetics
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Tandem Mass Spectrometry
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gamma-Aminobutyric Acid / metabolism
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Peptides
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RNA, Messenger
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Synapsins
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Synaptosomal-Associated Protein 25
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polyglutamine
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Glutamic Acid
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gamma-Aminobutyric Acid
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Dopamine