Photo courtesy of Frank Gaillard.

What is Huntington’s Disease?

Huntington’s disease (HD) is a degenerative disease that manifests in specific regions of the brain and affects around 1 in 10,000 individuals worldwide. People with HD exhibit movement abnormalities, personality changes, psychiatric problems, and cognitive disabilities.

HD is an autosomal dominant genetic disorder, meaning that HD patients with one copy of the HD mutation have a 50% chance of passing this disease to their offspring. HD is most commonly diagnosed in adults between 30 and 50 years of age, however approximately 16% of HD cases affect juveniles and manifest before the age of 20.

Patients with HD typically live between 10 and 20 years after the appearance of symptoms. Common causes of death in HD patients are not due to HD itself, but rather to unrelated medical problems such as infection, choking, or pneumonia.

What Causes Huntington’s Disease?

In 1993, scientists identified the genetic factor that causes HD, a mutation in a gene called Huntington (HTT) located in human chromosome 4. The exact function of the Huntingtin protein remains unknown, however it is important for proper brain cell development and function, intracellular transport, and transcriptional regulation.

The HD mutation is an expansion of DNA within the first exon of HTT comprised of CAG trinucleotide repeats which produce a poly-glutamine (PolyQ) tract in the huntingtin protein. Normal individuals have less than 30 CAG repeats while HD patients typically have 36 or more. The HD mutation is dynamic, meaning that the number of CAG repeats can expand when passed from generation to generation. The more repeats an individual has, the more severe the HD phenotype and the earlier the onset of symptoms.

The presence of extended CAG repeats in the Huntington gene causes a dysfunction of the mutant huntingtin protein (mHtt), which disrupts normal cell processes and transcriptional events. Medium spiny neurons are the main type of cells affected by mHtt. Since they are located in the striatum of the forebrain, this is the area that degenerates in HD patients (Figure 1).

Treatments and Cures

Presently, there are no cures for HD or treatments to halt HD progression. Current therapeutic approaches, such as anti-psychotics and anti-depressants only partially help with symptoms of HD without helping to change the course of the disease.

Another avenue for HD therapeutic development is targeting expression of mHtt protein in cells. Recent technology developed by academics and ISIS pharmaceuticals targets mHtt expression using short interfering RNAs (siRNAs). ISIS engineered siRNAs that specifically target the mutant HTT gene and silence its transcription thus lowering the amount of mHtt protein in cells. Sangamo Biosciences has taken a different approach and is using genome engineering technology (specifically zinc-finger nucleases) to target the mutant HTT gene and reduce its expression in cells.

Disease of Aging

How is Huntington’s disease an aging related disorder? All neurodegenerative diseases are diseases of aging. Many individuals born with diseases such as Parkinson’s and Alzheimer’s are born with genetic mutations that cause their disease. However, in many cases, symptoms of their disease do not appear until later in life, and sometimes, like in many cases of sporadic Alzheimer’s, not until old age. In HD, all patients have the genetic mutation, but most only show symptoms as they reach middle age (except for cases of juvenile HD).

As HD patients age, specific brain cells in major areas of the brain die off. It is thought that initially, these neural cells are able to cope with the stress caused by mHtt, but over time as the cells age, their ability to cope deteriorates and results in cell death.

What does the Future hold?

The future of Huntington’s disease research lies in understanding normal Huntingtin function in cells and how mHtt causes toxicity in specific types of neurons and HD pathology in human brains. If scientists can further elucidate the molecular signaling pathways involved in HD, they can identify new biological targets for therapeutic development and develop better methods to get rid of mutant Huntingtin in cells.

Additionally, stem cell research will play an important role in the advancement of HD research. Induced pluripotent stem cells (iPSCs) can provide an avenue for cell replacement therapies where scientists could transplant populations of healthy iPSC-derived neural cells into areas affected by degeneration to replace lost cell populations and restore proper brain function.