Huntington’s disease, a late-onset neurodegenerative disorder characterized by problems with movement, mental function and behavior, currently has no cure. But a new study provides hope, as researchers have identified a new therapeutic target for the disease.
The researchers, led by Prof. Gillian Bates and colleagues from King’s College London, in collaboration with a team of international scientists, published the results of their findings in the journal PLOS Biology.
The gene for Huntington’s disease (HD), according to the researchers, was discovered in 1993, and it has been puzzling the medical community ever since.
It affects approximately one person in 10,000, usually from about the age of 35, and the researchers note that patients normally die within 20 years.
Huntington’s disease is caused by a strange mutation in a gene that encodes a protein called “huntingtin.”
The researchers say these mutations then create long stretches of glutamine – an amino acid – within the protein chain, which prevents huntingtin from folding properly, making it “sticky.”
As a result of this, the huntingtin proteins clump together in the nucleus and the cytoplasm of cells, which disrupts facets of cellular function, leading to the death of nerve cells.
These so-called huntingtin aggregates interfere with the transcription of genes, say the researchers, and other research has shown that inhibiting a family of enzymes that regulate transcription – histone deacetylases (HDACs) – has beneficial effects for HD.
The problem is, however, that humans have 11 different HDAC enzymes, which makes knowing which HDAC to inhibit very tricky.
Prof. Bates and her team conducted their work in a mouse model with aggressive Huntington’s disease, and they pinpointed one of these enzymes – HDAC4 – as the target.
However, the researchers say that surprisingly, all the action is happening in the cytoplasm and not the nucleus. And the role of HDAC4 in transcription has little involvement.
By halving HDAC4 levels in the cells of HD mice, they found they could delay the clumping of huntingtin in the cytoplasm.
Additionally, they observed that reducing HDAC4 levels recovers the overall function of nerve cells and their synapses, producing improvements in movement, neurological performance and even lifespan of the mice.
The team adds that this all happens without any improvement in the nucleus’ defective gene transcription, which is in line with the cytoplasmic association between HDAC4 and huntingtin.
While the results are very promising, the researchers note that “it is still very early days and it is important to note that the medical applications of any therapy arising from this study have not been studied in a clinical setting.”
However, they do note that one inhibitor, suberoylanilide hydroxamic acid (SAHA), was previously shown to improve defects in the mouse model. This same inhibitor also decreases levels of the HDAC4 protein.
The team is therefore hopeful that developing HDAC4-targeted compounds could be a potential strategy to improve the lives of HD patients.
When asked about any future research, Prof. Bates told Medical News Today:
“Our current focus is to dissect the interaction between HDAC4 and huntingtin and to understand how a reduction in HDAC4 restores synaptic function and nerve cell connectivity in mouse models of Huntington’s disease.”
In early 2013, Medical News Today reported that a team from MIT found that the Huntington’s gene damages brain cell function by disrupting the on-off switching patterns of other genes.