Huntington's Disease is Associated With Stress Levels

Persistence of a marker of chronic cellular stress, that is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is also found to take place in the brains of Huntington's disease (HD) patients, as per a study at the University of California, published in the Journal of Clinical Investigation.

Huntington's disease (HD) is a rare, inherited and progressive neurodegenerative disorder that is characterized by the increased CAG repeats in the HTT gene on Chromosome 4. It usually strikes between the third and fourth decade of life.

‘Persistence of a marker of chronic cellular stress, previously associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is also found to take place in the brains of Huntington's disease (HD) patients. This would further enhance the understanding of stress biomarkers and their role in HD progression to formulate viable therapeutic avenues against it. ’

Abnormal accumulation of stress granules (SGs) - clumps of protein and RNAs that gather in the cell, generally occur as a response to chronic cellular stress. The present study has now identified that SGs are a pathological feature of HD. The abnormal accumulation of the granules is potentially found to be impacted by the extracellular vesicles - messaging system between cells in the brain and this could alter the behavior of other cells. The study also found one of the critical features of multiple neurodegenerative diseases - mislocalization of TAR DNA-binding protein 43 (TDP43).

Stress Markers and Huntington's disease "We were initially interested in whether the profile of these messages could serve as a biomarker for HD and investigated whether the vesicles from HD patients contain messages that are different from those of unaffected individuals," says first author Isabella I. Sanchez, Ph.D., from the Thompson Laboratory at UCI School of Medicine.

A key player in SG dynamics - GTPase-activating protein-binding protein 1 (G3BP1), was found as a predicted target and the messages to alter the production of proteins for SG formation was carried in the form of small non-coding RNAs (miRNAs) in CSF of HD patients.

"This finding regarding the miRNAs was very exciting, as we had simultaneously started investigations to characterize SGs in HD brain tissues. SGs can be very difficult to detect in brain tissues, and it just so happened that we had narrowed down the adequate conditions and were ready to being characterizing G3BP1 SGs in HD mouse and HD patient brains," says Leslie M. Thompson, Ph.D., Donald Bren and UCI Chancellor's Professor in the Departments of Psychiatry & Human Behavior and Biological Chemistry at the UCI School of Medicine, and Neurobiology and Behavior at the UCI School of Biological Sciences.

The study thereby highlights the finding that the SG pathology in HD may result from an accumulation of G3BP1 SGs that initially served a protective function, but develop into hyper-stable structures over time.

These data would further enhance the understanding of SG accumulation in HD progression and formulate viable therapeutic avenues against it.

Source: Medindia