Genetics of Parkinson's - Why, What and How


by Andrew Singleton, PhD

WHY? There are several basic ideas underlying the investigation of genetics in Parkinson's disease (PD). The first is that identifying genetic mutations that cause PD allows researchers to make models of the disease both in cells and in animals. By studying these models we can gain insight into the molecular and cellular basis of the disease. All of this is ultimately aimed at developing a therapy that halts or reverses the disease progression, not just one that treats the symptoms. A second main outcome of genetics work is that it allows the identification of subjects who are at risk for the disease. In the long term this allows monitoring of patients, and when preventative therapies are developed, to provide early treatment. From a clinical research perspective, having a pool of individuals who we think are at greater risk for PD but who do not yet have obvious symptoms of the disease, is incredibly valuable; it allows continued study of these people over many years, with the aim of defining symptoms that belie the onset of Parkinson's disease years before any movement disorder is felt by the patient. Early identification of the disease will be critical in the effective application of preventative therapies.

WHAT? Given that so much emphasis has been placed on identifying genetic changes that underlie PD, what have we found? The last decade has been a successful one for PD genetics. 1997 saw the identification of the first genetic mutation to cause PD in a gene that produces the protein a-synuclein. This was a monumental discovery for many reasons: it showed that genetic study of PD was possible; it provided researchers with a window into the disease; and perhaps most importantly, it brought rare and familial forms of PD closer together. A common and reasonable criticism was that familial forms of PD may bear no relationship with typical sporadic PD. The onset of the familial form is often younger, there are clinical features that differ, and of course most obviously, there is a clear familial aspect to the disease (positive family history used to be exclusionary in the diagnosis of PD). However, the finding that the protein a-synuclein was a major component of the hallmark lesion in all PD cases, not just familial PD, really tied the familial and sporadic forms of the disease together. This initial finding has been followed by the discovery of four other genes that can cause PD when mutated, PRKN (also called parkin), DJ-1, PINK1 and LRRK2 (also called dardarin). The two most common genetic causes of PD are mutation of parkin and of LRRK2; however, these are still a relatively rare cause of PD. Parkin mutation appears to be responsible for 20% of youngonset PD where patients have a strong family history of disease and onset below 30. Mutation of LRRK2 seems to underlie~2% of typical late onset PD. Research using these discoveries to delve into the mechanisms of disease is really beginning to mature, and as a field we are beginning to get a more cohesive picture of what PD is.

HOW? We are entering a new age in the field of genetics. The tools to find genes that underlie disease have become more sophisticated and more readily available. We are in a better position than ever to define the role of genetics in risk for PD, prognosis following onset and response to treatment. The successful application of these techniques requires several things, at least two of which involve those affected by PD. First and most obviously, these studies require the participation of patients and their family members. This can involve being enrolled within a study, being a vocal supporter of research or even serving on institutional review boards that assess the ethical considerations of proposed research projects. Second, they require patients and their families to seek out reliable information about genetics and to truly understand the impact genetics is likely to have not only on research but also on individual patients. I strongly encourage you to do this (i.e., speak to genetic counselors, movement disorders specialists, read articles and attend programs on genetics, etc.). Only through understanding these issues can we as a community move forward to a cure for PD.

Andrew Singleton is Chief, Molecular Genetics Unit, National Institute on Aging(NIA), National Institutes of Health(NIH) in Bethesda, Maryland.

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