An Antibody to Phospho T3 of Human Huntingtin

Tech ID: 27371 / UC Case 2016-335-0

Brief Description

Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by abnormal function of mutated Huntingtin protein. The invention uncovers an antibody to a new post-translational modification site that affects human Huntingtin aggregation and pathogenesis of HD.

Full Description

Huntington’s disease (HD) causes neurodegeneration is specific tissues when widely expressed Huntingtin (Htt) protein is mutated to contain an expanded polyglutamine (polyQ) region in the N-terminal fragment of Htt. These Htt fragments seem to modulate disease progression as evidenced by such fragments found in post mortem brain tissue of HD patients and within exon 1 of Htt, which is sufficient to cause HD in animals. Exon 1 of Htt encodes 17 highly conserved amino acids followed by a polyQ repeat of variable length and ending with a proline rich domain of 50 amino acids. Considering how Htt exon 1 causes pathology and contains several modifiable amino acid sites within its protein sequence, discovering post-translation modifications in this fragment may reveal key modulators of HD.

The protein context surrounding the polyQ repeat appears critical for modulating neurodegeneration. Any post-translational modification of the flanking protein sequences can influence this protein context. Post-translational modifications of a protein can affect activity state, intracellular localization, turnover rate, and protein-protein interactions. Several modifications of Htt, without exogenous modifiers, have been identified and implicated in HD, but presently none of these occur within the pathogenic Htt exon 1 fragment.

UCI researchers used mass spectrometry and identified the first amino acid site in this Htt fragment as a modification target. They found 1. specific phosphorylation sites on endogenous Htt in vivo, 2. modified human Htt is affected by polyQ expansion and cell type, 3. this modification produces less Htt aggregates in vitro and in vivo, and 4. mutating the modification site by substituting similar but distinct amino acid residues rescued Htt-induced lethality and neurodegeneration in Drosophila HD model. Consequently, the researcher developed a phosphorylation-specific antibody to modified human Htt. Therapeutic strategies that enhance such modification events could affect HD pathogenesis.

Advantages

 

  • Novel antibody for detecting modified human Htt
  • Phosphorylation-specific antibody enables highly specific modification tracking in tissues
  • Identifying pathways enhancing this modification may provide a promising approach toward therapeutic development

 

State Of Development

§ Discovered post-translational modification sites on Htt fragment

§ Developed a new phosphorylation-specific antibody to modified human Htt

§ Demonstrated the modification occurs on full-length, endogenous Htt in vivo and affects aggregation and pathogenic properties of Htt

§ Found that length of polyQ tract affects the relative abundance of this modification

§ Mutating this modification site led to Htt aggregation in vitro and in vivo

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