Targeting a protein fragment may slow Huntington’s progression: Study
Scientists find small piece of huntingtin protein triggers disease in mice
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A small fragment of the huntingtin protein, called HTT1a, may play an important role in the development of Huntington’s disease, the findings of a mouse study suggest.
According to the scientists, this protein fragment was seen to trigger the disease in the mice.
When researchers blocked the production of this small fragment in the brains of a Huntington’s mouse model, the expected clumping, or aggregation, of the mutant huntingtin protein (mHTT) — which is thought to drive Huntington’s-related neurodegeneration — was reduced and delayed, the team found.
“These data demonstrate that the production of HTT1a initiates [mutant huntingtin] aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies,” the scientists wrote.
Titled “The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington’s disease,” the study detailing the work was published in the journal Brain by a team of international researchers.
A progressive disease, Huntington’s is caused by changes in the HTT gene, which results in a DNA sequence called CAG being repeated too many times. This leads to the production of a mutant huntingtin protein, known as mHTT, that is longer than normal and tends to form toxic clumps in brain cells.
Investigating the exact mechanisms that drive Huntington’s
While it’s believed that these clumps cause nerve cell dysfunction and death in people with Huntington’s, the exact mechanisms underlying them are still unclear.
Excessive CAG repeats are unstable and can lengthen with time in certain nerve cells — a process called somatic CAG expansion. This ongoing growth is believed to contribute to Huntington’s, as longer CAG repeat segments are linked to earlier symptom onset and more severe progression.
An expanded CAG repeat can promote the production of HTT1a, a short fragment of the huntingtin protein that is especially prone to clumping. The longer the CAG repeat segment, the more HTT1a is made.
“Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its [disease-causing] consequences?” the researchers asked in their study.
“Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels,” the team wrote.
To find out, the researchers studied both healthy mice and a mouse model of Huntington’s that carries a large CAG repeat expansion. Both groups contained some animals genetically modified to prevent HTT1a production. All mice were followed for up to 17 months, or nearly 1.5 years.
Initial experiments confirmed these modifications. That is, all mice produced the full-length huntingtin protein — both healthy and mutant — across different brain regions, such as the cortex, the striatum, and the hippocampus.
However, levels of HTT1a protein decreased with age in the Huntington’s mouse model, due to recruitment into huntingtin clumps, and the protein was barely detectable in Huntington’s mice modified to prevent HTT1a production, according to the researchers.
When assessed over time, mHTT clumping occurred much later in the brains of Huntington’s mice lacking HTT1a, and clumps were smaller and less widespread. While HTT1a was still detected in mHTT clumps of these mice, it was found at much lower levels and later than in unmodified mice with Huntington’s-like disease, per the team.
Reducing protein seen to correct abnormal gene changes
The production of mHTT is known to disrupt gene activity, which is thought to drive early, widespread nerve cell dysfunction in Huntington’s. In Huntington’s mice, many genes in key brain regions, such as the striatum and hippocampus, showed abnormal activity as early as 6 months, when mHTT clumps were also detected. Further, the number of affected genes increased over time, according to the researchers.
When HTT1a was reduced, 25% of the abnormal gene changes in the striatum were fully or partly corrected at 6 months of age. By 12 months, or the one-year mark, 40% of dysregulated genes in the striatum and 52% of those in the hippocampus were fully or partly corrected, the researchers reported.
Finally, the team measured biomarkers in spinal fluid and blood that are commonly used to track nerve damage and inflammation in Huntington’s. These markers were elevated in the spinal fluid of unmodified Huntington’s mice but remained at normal levels in those with reduced HTT1a, the team found.
“This complete rescue of the [spinal fluid] biomarkers had occurred despite the fact that more than 50% of the Huntington’s disease [gene activity] signature remained dysregulated,” the team wrote.
These data support the hypothesis that HTT1a contributes significantly to Huntington’s disease [development]. … [The findings] strongly support targeting HTT1a in the design of therapeutic approaches to lower huntingtin.
The researchers noted that many experimental therapies for Huntington’s aim to lower overall huntingtin protein levels. However, they also reduce the healthy form of the protein, raising safety concerns. Targeting HTT1a specifically could offer a more focused approach to prevent mHTT clumping and slow disease progression, according to the researchers.
“These data support the hypothesis that HTT1a contributes significantly to Huntington’s disease [development],” the team wrote. The findings also “strongly support targeting HTT1a in the design of therapeutic approaches to lower huntingtin,” the researchers added.
Overall, this work adds to an increasing number of preclinical studies showing that molecules designed to reduce HTT1a may be “much more beneficial than lowering full-length HTT alone,” the researchers wrote.
