Clue to Onset and Progression of Huntington's Disease is Discovered
18 May, 2007 11:27 am
Huntington?s Disease is a devastating neurodegenerative genetic disorder which affects particular areas of the brain, progresses with time and worsens in successive generations. The disease typically manifests in midlife in individuals who inherited faulty gene. There is currently no cure available.
HD gene is responsible for production of the protein called huntingtin. Expansion of the segments in the gene makes huntingtin protein toxic to cells. Although abnormal gene and huntingtin protein are present in every cell of the body, only cells in two specific regions of the brain experience toxicity which eventually cause them to die. This significant cell loss results in deterioration of brain functions which include control of movement and emotions and underlie intellectual abilities.
For a number of years researchers worked to develop different model organism systems to mimic Huntington’s disease in order to answer important questions: when does expansion occur, why only a subset of cells in brain becomes affected and dies and how cells escape safeguard mechanisms designed to correct errors in DNA.
It has been known for some time now that initially expansion, a change in a number of repeated segments, in HD gene occurs in the germ cells of a parent and the abnormal gene is passed to an offspring. Mouse engineered to harbor human HD gene with long stretch of repeated segments mimics the disease and has helped to discover a “second hit” to the region. That is a continuous increase in number of segments in brain cells with age. Earlier studies suggested that degree of degeneration of affected brain regions and onset of the disease are dependent on a number of repeated segments in HD gene. Both the inherited expansion and an increase in length that is observed in brain cells neurons with age are believed to contribute to toxicity.
The underlying mechanism of expansion process has been a great deal of a puzzle for researchers in the field since the genetic defect was first discovered. Finding a mechanism will likely help to stop the disease in affected families and lead to a cure. A great effort has been put to answer what pathways in the cells fail to function properly and let expansion grow. The integrity of DNA, the fidelity of its synthesis and transfer from parent cell to daughter cell are guarded by sophisticated cellular machinery called DNA repair. DNA repair machinery recognizes and corrects DNA with various types of damage caused by encounter of DNA with different toxic substances, products of cellular metabolism.
In our studies using a mouse which harbors long number of repeated segments (similar to that found in human disease), we measured accumulation of DNA damage with age and showed that it correlates well with progressive expansion observed in brain cells neurons of these animals. We found that one particular DNA lesion which arises during a process called oxidation, present in each repeat segment, is a key to onset of expansion in brain cells neurons. We show that it initiates DNA repair response through its recognition protein called OGG1. OGG1 excises the lesion in attempt to repair DNA, and doing so promotes formation of DNA breaks, structures shown to be necessary precursors to expansion in germ cells. Over time, the number of lesions and DNA breaks in the brain overwhelms the repair system causing more expansion and leading to disease onset.
Gradual accumulation of oxidative damage which is recognized as a major cause of aging in aerobic organisms, and removal of the damage by OGG1 explains the progressive nature of the expansion in adult neurons, cells that do not regenerate.
Our observations suggest that blocking OGG1 protein may stop expansion and thereby delay onset and progression of toxicity in neurons. This could be a target for potential therapy. The finding for the first time provides a direct molecular link between oxidative damage and toxicity in brain via a DNA damage response. The discovered mechanism is likely to extend beyond Huntington’s disease and have general relevance to late onset neurodegeneration.
Reference:
Irina V. Kovtun, et al , OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells, Nature advance online publication, 22 April 2007
Very well written paper which may have a crucial long-term clinical impact on the treatment of Huntington's disease.