Neurology Central

Novel proteins linked to Huntington’s Disease

The genetic mutation in the Huntingtin gene present in Huntington’s disease patients may result in a ‘cocktail’ of mutant proteins capable of accumulating in the brain, a new University of Florida Health (FL, USA) study has suggested. The findings were presented recently in Neuron.

The team of researchers closely analyzed post-mortem brains of 12 individuals with Huntington’s Disease and identified five proteins in abundance in areas of the brain exhibiting neuronal loss, cell death and other key disease signatures such as neuroinflammation.

While one of the proteins contributing to the disease pathology had previously been associated with Huntington’s Disease, the four other key proteins were entirely novel. The investigation discovered that CAG, the DNA repeat mutation characteristic of Huntington’s Disease, was capable of undergoing repeat associated non-ATG (RAN) translation and consequently producing four additional damaging repeat proteins.

Surprisingly, the RAN proteins were produced without an associated signal within the genetic code, something previously thought to be essential for protein production. The characteristic long single protein or amino acid repeats were exhibited in all four of the RAN proteins.

“These repeat proteins are too long for cells to deal with and they build up as aggregated clusters that kill cells,” commented lead author Laura Ranum (University of Florida Health).

The RAN proteins were found to accumulate in the striatum frontal cortex, cerebellum and interestingly for the first time in the white matter. The researchers therefore believe that the RAN proteins could also be linked other similar neurodegenerative disease, including spinobulbar muscular atrophy and several types of spinocerebellar ataxia.

While identifying the novel RAN proteins in degenerated brain regions with no association to the Huntingtin protein has helped in making a crucial link to between the damaging proteins and the disease, the presence of four different damaging proteins as opposed to one in the disease also presents some challenges for fully understanding the disease pathology.

Ranum and the team now plan to investigate further the mechanism of protein production without the expected cellular signalling as well as potential techniques for blocking their creation.

Ranum summed up: “We have to get to the bottom of why these junk proteins accumulate in the brain and we need to figure out how to block that process.”

Source: University of Florida Health press release