Introduction to Parkinson's Science/Q Page 120

Is Parkinson's disease inherited?

Summary

Parkinson's disease is inherited in a classic "Mendelian" way in only a few rare families. However, great insight can be gained into what goes wrong in Parkinson's by studying the mutated genes in these families. Most cases in the general population are "idiopathic" (without known cause) but this doesn't necessarily mean there is no underlying genetic cause; it is just harder to identify. Parkinson's is a genetically complex disease.

Introduction to Genetics

Genes and chromosomes are made of DNA and carry the inherited information that made you

For centuries people have noticed that offspring resemble their parents. It wasn’t until Gregor Mendel’s experiments on pea plants in 1863 that the reasons why this happens first became clear. Mendel demonstrated that the structure and function of biological organisms (their “phenotype”) is inherited in discreet units (collectively called the organism’s “genotype”) that are preserved from generation to generation.

The most basic unit of inheritance is the gene. There are many genes in biological organisms; for example, 30,000 in humans. Two copies of every gene are present in each of us and we inherit one copy from our Mother and the one copy from our Father.

The next largest unit of inheritance are chromosomes, which are made up of many genes. In humans, there are two copies of almost every chromosome; in one individual there are normally 22 pairs of “autosomal” chromosomes and one pair of “sex” chromosomes. Females inherit two copies of the X chromosome (as well as all autosomal chromosomes) whereas males inherit all 22 pairs of autosomal chromosomes but only one X along with one Y chromosome. The full complement of genes and chromosomes is called a ”genome”.

Genes (and therefore chromosomes) are made up of a chemical called deoxyribonucleic acid (DNA). DNA comprises four chemical bases, A, T, C and G, arranged in a double helix structure. Each gene is made up of different combinations of these bases, which make distinct proteins and proteins form the building blocks of cells. The human genome is made up of 3 billion chemical bases and genes are separated from each other by long stretches of DNA that doesn’t make protein.

Genes can change over time by accumulating “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). Mutations mainly occur by damage inflicted on DNA by others chemicals or errors when DNA is replicated. Our close relatives share most of our mutations with us, while distant relatives do not.

In general, diseases with a genetic basis are classified as either “dominant” or “recessive” and are caused by dominant or recessive mutations respectively. We only have to inherit one copy of a dominant mutation to manifest a disease; therefore 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.

Discovering disease genes

Scientists find mutations in DNA by mapping the genome and gradually narrowing the search until eventually a gene sequence is read. It's like looking for a needle in a haystack.

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

Bigger genetic affects are easier to see and study

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 a cumulative 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 every gene of affected individuals. This identifies lots of mutations but most will not be responsible for the disease. A laborious process of validation in cells will have to take place to identify causative mutations.

Understanding the effect of mutations

It is crucial, once a mutation has been found, to study what effect it is having

It is not enough to just identify a disease causing mutation. Further work is needed to understand what effect the mutation is having on the normal function of the gene. Is it abolishing the function of the protein made by the affected gene or just diminishing it? It is also possible for mutations to make the protein hyperactive or take on a new function altogether. 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 people with mutations? 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

Understanding the effect of mutations on the normal function of disease genes

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 in the brain 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 (energy producers of the cell) less able to cope with oxidative stress (a natural effect of energy production), leading to cell death and loss of nerve cells in the brain

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.

Related Pages

PD Inheritance

References