Genetics of Parkinson's disease

Important things to note:

A “genome” is all the genetic material that makes a living organism; genetic material is made up of DNA, comprising four chemical bases A, T, C, G; a “gene” is a string of A, T, C, Gs with a distinct function. The human genome is made up of 3 billion chemical bases arranged into 30,000 genes. We inherit two copies of each gene and genes make proteins.

We all carry changes in our genetic material called mutations; for example, a normal gene, AATTCCGG, can be mutated into AAATCCGG (the first T has changed into A). Most mutations are harmless but some disrupt the function of genes (e.g. they can alter the protein made by the affected gene). Our close relatives share most of our mutations with us, while distant relatives do not.

Discovering disease genes

Most of the mutated genes identified as causing a disease are found in rare families with lots of affected close relatives. This suggests that the same causative mutation is in each affected family member but missing in those unaffected by the disease. Studying these families has the great advantage of reducing the number of genetic changes that could be causing the disease because each family member will carry similar mutations; the needle is in a smaller haystack. In contrast, there are many different mutations in the general population, making it very difficult to identify the causative mutation by studying whole populations; the haystack is huge!

To identify disease genes, the genome is “mapped” to discover regions shared in affected but not in unaffected family members. This is done by identifying distinct motifs or signatures in the sequence of DNA (e.g. AT repeats, ATATATAT) in known regions of the genome; if these motifs are shared among affected individuals then genes within this region are more likely to carry the causative mutation.

Once a region has been identified the genes within that region can be read (by DNA sequencing), revealing any mutations. If a mutation is found only in affected family members, it is likely that the mutated gene is important in causing the disease.

The difficulty of subtle genetic effects

The procedure for identifying disease genes just described is powerful when the mutation has a large genetic effect; there is a direct link between the mutation and the disease. However, in complex diseases, such as Parkinson’s, mutations are likely to have an indirect link to the disease and exert a more subtle genetic effect (regions containing mutations are likely to be missed when mapping). For example, it is possible that Parkinson’s disease is caused by lots of mutated genes, each with a small effect, coming together and exerting an accumulative effect. This complex inheritance is very difficult to untangle; there are many different haystacks to search. One way to identify multiple genetic factors is to sequence whole genomes of affected individuals. This generates lots of potentially causative mutations which have to be sifted to discover the mutations responsible.

Understanding the effect of mutations

It is not enough to just identify a disease causing mutation. Further work is needed to understand what affect the mutation is having on the normal function of the gene. Is it abolishing the function of the protein encoded by the affected gene or just diminishing it? It is also possible for mutations to make the protein hyperactive. To understand how the altered gene function is causing a disease the context of the cell must be considered; does the protein normally interact with other proteins and is this disrupted by the mutation? Does the protein switch on a particular function of the cell and is this missing in mutants? Mutations do not happen in isolation; they occur in and potentially affect the complex functions of the cell. If genetic diseases are to be understood and tackled by new medication, it is crucial to understand what the mutation is doing to the normal function of the cell.

Genes identified in Parkinson’s

Genetic diseases come in two different varieties, dominant and recessive. Dominant disease occurs when a dominant mutation is present in only one copy of a gene. In contrast, a recessive mutation needs to be present in both copies of a gene to cause a recessive disease.

Progress has been made in identifying both dominant and recessive mutations that cause Parkinson’s disease:

α-synuclein – dominant mutations cause inappropriate clumping of α-synuclein protein into Lewy bodies, a common feature of nerve cells affected by Parkinson’s

LRRK2 – dominant mutations cause LRRK2 protein, which normally interacts and carefully switches on other proteins, to activate proteins inappropriately.

Parkin – recessive mutations disrupt the control Parkin protein exerts on the levels of particular proteins in the cell

DJ1 – recessive mutations make mitochondria (the power plants of the cell) less able to cope with oxidative stress, leading to cell death and loss of nerve cells

PINK1 – recessive mutations affecting PINK1 protein, like LRRK2, cause inappropriate activation of other proteins

All of the genetic causes of Parkinson’s somehow (this is currently unknown) cause the death of dopamine producing nerve cells in the substantia nigra.

dr jonny

Dr J - awesome round-up of the subject. Very useful.

And Bartobob - very good article, I shall print it off to enjoy reading at my leisure.

thanks to both of you,

Hi have the inherited type of PD, which I inherited from my fraternal Grandmother. As far as I know she is the only other person in our family who had PD. No one in my fathers generation developed PD and I am one of 15 cousins in my generation yet I am the only one who has developed PD. I was diagnosed when I was in my early twenties, I am 60 years old now.

Hi Blue Angel,

If you are interested in genetics I found "50 Genetics ideas you really ought to know" by the science editor of the Times Mark Henderson puts across the concepts in a very clear way.

Hi Blue Angel

The inheritance of Parkinson's disease is very complicated. Except in the very few families worldwide with a demonstrated genetic cause, inheritance of Parkinson's is largely unknown. I can think of a few scenarios to explain your situation (all are hypothetical):

1. You happened to inherit the same rare configuration of genetic causes as your Grandmother. Maybe your other family members inherited one or two but not enough to cause Parkinson's

2. A new mutation occurred in you to cause your Parkinson's

3. Maybe you and your Grandmother were exposed to something in the environment and since you were both genetically susceptible this resulted in Parkinson's

4. Maybe unaffected family members have a mutation which lessens the impact of the mutation you inherited

I'm sorry I can't give you a definite answer. The complexity of the situation and the state of current knowledge have yet to match up

dr jonny

I thankyou too Dr Jonny for that very detailed but succinct explanation .

I developed PD in my 50's and was diagnosed around the same time as my youngest brother ( also in his 50's). I am one of 5 siblings. No other family member in our extended family has had PD that we are aware of. I trace my ancestry back about 200years.

Could you explain possible inheritance as you did above.

Dear Hikoi

I can't say for sure but I can speculate: -

Because mutations are rare it is more likely that affected close relatives share the same mutation, meaning that the same gene is faulty in you and your younger brother. Since you have no past family history the mutation probably occurred in the recent past (i.e. one of the past few generations of your family). It is important not to blame anyone for passing the mutation to you. Nobody has control over the genetic inheritance they give to their children. Also, mutations are truly random events.

I hope this helps

dr jonny

Thankyou for your reply dr jonny
I was particularly wondering if it is likely to be a dominant or recessive gene responsible.
Yes i agree with your caution about blame, i feel very relieved both my parents died before our diagnosis. It is possible they would have felt guilt (inappropriately) and i am so pleased that never happened.

Dear Hikoi

We inherit two copies of each gene (one from our Mother and one from our Father). We only have to inherit one copy of a dominant mutation to be affected so dominant disease tends to be in each generation. Two recessive mutations are needed for a recessive disease; since mutant genes are rare and their bad effect is stopped if you inherit a non-mutant copy of the gene as well, recessive disease tends to miss generations.

However, this is complicated by what is called "incomplete penetrance"; two people inherit the same dominant mutation or the same two recessive mutations but only one person gets the disease. Other factors are subduing the bad effect in the unaffected person. Humans inherit 30,000 genes (two copies each); imagine these 30,000 genes are in a big hall talking to each other. The dominant mutant genes are clearly heard above the general hum of the conversation. Recessive mutant genes are quieter and need to join with their partner to get their voice heard. Sometimes, however, other genes can shout down these mutant genes to make them less effective in controlling the conversation.

Sorry for the long preamble - because your generation seems to be the only one affected its difficult to say whether you and your brother have recessive or dominant mutations; siblings can be affected in both situations. Also, as I've tried to explain, others factors can complicate classic "Mendelian" inheritance.

dr jonny

Thankyou very much for that explanation. Very helpful. As i now am slightly cognitively challenged i have copied it so i can read it again when i have forgotten the content.