Massive inflammation and other changes in the striatum, an area of the brain selectively destroyed in Huntingtons disease (HD), are already present before patients develop any symptoms, a study has found.
These findings could help understand how the disease unravels and why this brain region is particularly sensitive to degeneration in individuals with Huntingtons.
The study, The caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal Huntingtons disease brain, was published in the journal BMC Medical Genomics.
Huntingtons is a neurodegenerative disease caused by mutations in the huntingtin(HTT) gene and marked by trouble in controlling movement, a progressive loss of thinking ability, and psychiatric problems.
Symptoms, which typically begin when people reach their 30s and 40s, stem from a selective degeneration of certain brain regions, particularly two areas: the basal ganglia, a region deep in the brain thats responsible for functions including movement coordination; and the cortex, the outer and highly twisted layer of the brain which controls thought, behavior, and memory.
Within the basal ganglia, HD targets nerve cells (neurons) of the striatum, especially in two areas known as the caudate nuclei and putamen. These regions can shrink and suffer massive damage as a result of disease progression.
Very little is known about the active disease processes leading to such debilitating symptoms. Obtaining post-mortem brain samples from people with disease-causing mutations who have not yet developed symptoms in other words, still have a largely intact striatum is very rare.
Researchers atBoston University School of Medicine (BUSM) had the opportunity to analyze samples from the striatum more precisely, the caudate nucleus of two HD-positive individuals who had no symptoms at the time of their death.
To pinpoint early drivers of disease, the team compared the activity (expression) of genes those turned on and turned off in the caudate nucleus of these asymptomatic individuals to the prefrontal cortex of 26 symptomatic Huntingtons patients and 56 healthy controls.
Researchers used a high throughput sequencing technology called RNA-Seq to determine gene expression profiles, and a preformed bioinformatics analysis to understand which genes and biological processes were altered.
Our data suggest that the striatum experiences massive inflammation in HD even before symptoms appear, and exhibits a similar gene expression pattern to that observed in prefrontal cortex. Patterns unique to the striatum are also observed, Adam Labadorf, PhD, director of BUs Bioinformatics Nexusand the studys senior author,said in a news release.
In addition to extensive inflammatory processes, the data also suggested that over the diseases course, the striatum undergoes some form of neurogenesis, or the generation of new nerve cells.
While these are only trends that warrant further investigation, researchers propose that active production of neurons could be happening in the striatum during the prodromal phase (before symptom onset) to compensate for the nerve cell loss that precedes symptoms.
The idea that active neurogenesis occurs in the adult brain is controversial, but could lead to exciting discoveries into the innate regenerative capabilities of the central nervous system, Labadorf said.
According to researchers, these findings provide clear evidence that the caudate nucleus is strongly affected in people positive for Huntington disease, before the emergence of any symptoms.
This study presents the most detailed analysis to date of the active disease process in the primarily affected brain region of HD, and although these results do not directly suggest any novel therapies, a better understanding of these processes is likely to lead to them, Labadorfadded.
An important observation was that some genes, like HSPA6, were perturbed across all HD patient samples relative to healthy brains. This set of genes may provide an opportunity to develop prognostic tests for disease progression, the researchers noted.
A robust clinical test measuring disease progression will likely take the form of a panel of key inflammatory and possibly developmental genes measured in the blood or cerebrospinal fluid (the liquid surrounding the brain and spinal cord), they wrote.
Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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