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Dr. Gosal's Articles: PD Genetics - a Review | What Causes Parkinson's?

The Genetics of Parkinsonís Disease: A Brief Review for the Uninitiated.

Dr. David Gosal

Parkinsonís disease (PD) is the second most prevalent neurodegenerative disorder with roughly 1% of the population affected being under 50 years of age. Roughly 5,000-6,000 people are affected in Ireland. It is characterised by the clinical triad of tremor, rigidity, and bradykinesia. These are ameliorated by dopamine administration.

Parkinsonís Disease is a complex disease with predisposing genetic and environmental causes. Traditionally, researchers have concentrated on environmental susceptibility factors such as

  1. viruses (Encephalitis Lethargica influenza outbreak, 1916),
  2. drugs (MPTP, a heroin substitute taken in 1960s), and
  3. various other agents such as pesticides, heavy metals, well water, and rural living just to name a few.

Environmental influences have always been difficult to prove, due to the fact that these factors were in the first instance ubiquitous (i.e. large parts of populations were exposed to these factors), hence it was difficult to get controls who had no exposure to suspected agents and, secondly, large studies are needed to prove associations (that are at best weak) which are both expensive and time consuming. It is likely that an individual would need an exposure to one or more such agents in combination with known/unknown genetic factors to express disease.

Traditionally, genetic factors were not in general considered important, due to twin studies which showed apparent little or no increased risk of the second twin developing PD if one was affected. Ultimately, these studies were proven to be flawed in design and execution, and are refuted by recent longitudinal twin studies. To further back this up, 10% of individuals with sporadic PD seem to have a positive family history of disease, and longitudinal studies have suggested that a family history of PD is an important contributor to risk of developing disease.

The relatively recent discovery of mutations in 4 genes ( a-synuclein, parkin, UCH-L1, DJ-1) - and, to date, seven other areas in the human genome - has rekindled interest once more in the genetics of PD. Although very interesting and exciting, they currently account for only a small percentage of disease - usually of young onset with a family history. Although recently they are being associated with older ages of onset, and in non-familial cases, none the less they have given us tantalising glimpses into the molecular pathways involved in neurodegeneration. We know from a number of these altered genes that they encode for proteins that are crucial for recognising and excreting waste products from neural cells. This may provide an attractive therapeutic target for future pharmacologic therapies.

Quite recently it has been shown that not only pathological mutations, but even certain polymorphisms, that is, different copies of the same gene (a lot of genes can have various normal forms, which contributes to the immense genetic diversity that is in the human genome) can be associated with PD. It is important to remember that by ďassociationĒ we do not mean that these specific polymorphisms directly cause the disease, but that for some reason they are found more frequently in diseased individuals.

Two genes have been implicated to date, namely a-synuclein and tau. What we do not know is exactly how this susceptibility arises, as many normal people also have these particular copies. Nor do we know exactly how much it contributes to PD as a whole in the population. It is very likely that there are very many more genetic susceptibility factors at play, that probably interact with each other and with environmental agents.

It is clear from the above comments that the neurodegenerative process is complex and that we havenít reached the proverbial iceberg never mind even exposing its tip! Many years of painstaking genetic research will be needed to tease apart the relative contributions of environment and the gene in the development of this disease.


  • Dr. Timothy Lynch, Neurologist, Dublin
  • Dr. Mark Curran, Neurologist, Belfast
  • Dr. Tim Counihan, Neurologist, Galway
  • Dr. David Gosal, Research Registrar to Dr. Lynch, Dublin
Currently, we are attempting to do exactly this. Ireland on the whole is an ideal country to conduct genetic studies, as one needs relatively large families and a well defined, racially homogenous population. To date, relatively isolated populations such as those that exist in Scandinavian countries, and certain parts of Europe have been used. If anything, we are probably more suited.

Parkinson's disease is a complex disorder with likely environmental and genetic contributions in every individual. Despite many years of painstaking research, little has been found. Hopefully, in partnership with other countries in Europe and worldwide who are currently piecing together other pieces of this puzzle, we can see the whole picture, or at least large parts of it. It is only through this basic understanding of the condition that we can effectively develop strategies that will lead to methods of, not only halting this disease in its tracks, but perhaps even effecting a cure.

A pilot study was undertaken last year here in Ireland, in which 140 patients were examined, all under 60 years of age. Of these, 40 individuals were analysed genetically. The results of this study will be published shortly. Given the success of this pilot study, we wish to expand this research project to include individuals from all corners of Ireland, and individuals of all ages.

In terms of our study, we are particularly interested in individuals with a family history, or age of onset of less than 60 years of age, but we would love to hear from anybody interested in participating. We know that a sizeable number of you have already participated in this study, and to you we give our heartfelt thanks! To the others with Parkinson's disease who have not yet contributed 5 mls of blood: we would strongly encourage you to participate and help Irish research into Parkinson's disease make real progress! All this study entails is freely donating 5mls of blood and answering a simple questionnaire.

We are also interested in individuals participating who do not have the condition and who have no family history of Parkinson's disease. We are using these individuals as a comparison group (Controls).

If you would like to participate, please contact us at the following E-mail address:


Or print out this form:

postal form

and send it to:

David Gosal, Research Registrar to Dr. Tim Lynch, Suite 1, Mater Private Hospital, Eccles Street, Dublin 7.

March 2004

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