PD-linked Genes Gather on Chromosome 1

Researchers have found three new regions in our genetic make-up which may contain vital evidence as to the cause of Parkinson’s disease (PD). A report on the discoveries was released this summer by the National Institute for Neurological Diseases and Stroke (NINDS). (www.ninds.nih.gov)

An intriguing aspect of the discoveries is that these three regions lie on the same chromosome. (There are 23 pairs of chromosomes in every cell of the human body.) More specifically, they lie on chromosome 1, in close proximity to each other. This fascinating finding is considered to be an interesting target for further intensive research by scientists seeking the cause of and a cure for PD.

Chromosomal regions that can be associated with a specific disease are often named after that disease. The specific new areas connected with Parkinson’s have been assigned the names of PARK 6, PARK 7, and PARK 10. They are additions to the previous findings of PARK 1, 2, 3, 4, 5, and 8. Clearly researchers are making tremendous headway in discovering the underlying cause of PD, and in only a short amount of time.

The medical research community has long believed that there is a hereditary component of PD, and many researchers have been examining hundreds of genes in human DNA to identify those specific to PD. Genes can be thought of as instructions to our cells to tell our body how to function properly, and they are packaged together in the chromosomes. In the study of genetics, the medical records and the genetic makeup of families with specific diseases from around the world are examined for a common factor that will reveal the underlying genetic cause of the disease.

This was exactly how PARK 1, the first region associated with PD, was found. In 1997, mutations in PARK 1 were found in large families of Italian and German origin. PARK 1 is associated with the protein alpha synuclein. At the time of the discovery, scientists had no idea how this protein functioned or why it was important to the study of PD. After much research, alpha synuclein deposits called “Lewy Bodies” were found in the brains not only of people with PARK 1 mutations, but also of those individuals who had PD that was not thought to be associated with specific genetic change (called sporadic or idiopathic PD).

PARK 6 was the first region on chromosome 1 to be associated with PD, and was found in an Italian family of sixteen with tremor- predominant PD. Symptoms started between the ages of 32 and 48 with asymmetry (symptoms mostly occurring on one side of the body), slow progression, and a good response to L-dopa (the leading treatment for PD patients). No one in the family had dystonia (involuntary muscle contractions) or dementia.

The second region, PARK 7, was found in a family of four from the Netherlands. They too had asymmetric PD with slow progression and a good response to L-dopa. Only one family member had tremor. Two members had dystonia, and three members had behavioral or psychiatric changes. This family also developed symptoms slightly later in age than that associated with PARK 6 - between 38 and 50.

Most recently, PARK 10 was discovered in a large study in which 51 families from Iceland, including 117 individuals with PD and 168 of their relatives, were investigated. Affected family members had similar symptoms to those in families associated with PARK 6 and 7, but had a later age of onset and no PD-associated dementia.

The contribution of families with many members affected with PD allowed these new regions to be identified. A combination of subtle genetic factors and non-genetic (environmental) factors probably cause PD in the majority of individuals with PD — most of whom do not have the genetic form of the disease.

However, the study of PARK 6, 7, and 10 is important because understanding the genetic cause of a disease is the very first step in determining the biochemical processes that eventually lead to the development of the disease. Diseases can occur when changes or mutations in genes cause the body to malfunction. When we fully understand how the disease pathway works, then scientists can try to block steps in the pathway, thereby preventing onset of the disease. Sometimes these interventions merely slow the progression of disease, or decrease its severity, but sometimes they result in a cure. Obviously, even slowing disease progression is a tremendous advantage for those affected with the disease.

The challenge for scientists is to understand not only the genetic cause of PD but the biochemical changes that take place in the brain as well. One aim of the research is to understand how changes in dopamine result in symptoms of PD. Dopamine is a neurotransmitter (or chemical messenger) important for movement, so people with PD are treated with dopamine replacement drugs, the most common being levodopa/carbidopa (commercially known as Sinemet). If scientists knew why and how this dopamine source gets depleted, then perhaps an intervention could be given years before symptoms even occurred! Perhaps PARK 6, 7, or 10 will be found to be associated with production or maintenance of dopamine. This knowledge would complete one more piece of the jigsaw puzzle and help solve the mystery of what causes PD.

Although dissecting this pathway is a long way off, every discovery helps. The hope is that the hotspots on Chromosome 1 will prove to be one more step forward on the path to curing PD.

For more information about genetic studies in Parkinson’s disease, please contact: Amanda Singleton
Clinical Research Coordinator
(301) 402-6231
adama@ninds.nih.gov