The role of genetics in Parkinson’s research

Research exploring the genetics of Parkinson’s has been crucial to understanding what drives the development of the condition. Whilst the causes of Parkinson’s are not yet fully understood, genetics can influence a person’s risk of developing Parkinson’s. Considering genetics is a vital part of the search for a treatment that could slow, stop or even prevent Parkinson’s.

A gene is a specific sequence of DNA, which contains the instructions for cells to make proteins. Humans have around 20,000 genes.

In Parkinson’s, the first gene to be identified and linked to Parkinson’s was the SNCA gene, in 1997. This gene holds the instructions for a protein called alpha-synuclein. Researchers uncovered that changes to the SNCA gene caused alpha-synuclein to misfold and stick together, creating clumps of protein. These clumps damaged surrounding brain cells, leading to Parkinson’s.

Although inheriting a change in the SNCA gene is very rare, found in fewer than 1 in 1,000 people with Parkinson’s, the findings demonstrated that genes did in fact play a role in the condition.

Since then, many different genes have been identified which are linked to Parkinson’s. Among them are the LRRK2 gene and the GBA1 gene, which are the most common genes to have differences known to increase the risk of Parkinson’s. 

The causes of the condition

A major challenge in Parkinson’s research is that the causes of the condition are not well understood. Genetic research has uncovered several genes that have changes which can be linked to Parkinson’s. Many of these changes cause problems in how cells function, and have helped researchers understand the underlying biology of Parkinson’s, whether genes played a role or not.

One gene linked to Parkinson’s is the PINK1 gene. This gene codes for the PINK1 protein, which is involved in the waste disposal system inside cells. When it functions correctly, the PINK1 protein helps clear away damaged mitochondria; small structures that produce energy for the cell. Changes to the PINK1 gene can mean that it stops doing its job, causing a build up of faulty mitochondria in cells. 

In people with Parkinson’s, this is a problem as a build up of waste can damage dopamine-producing brain cells, causing them to die.

Although a relatively small number of people with Parkinson’s (between 1 and 9% of people with young-onset Parkinson’s) have a change in their PINK1 gene, this understanding that mitochondria are affected is a relevant finding for the whole Parkinson’s community. Research has since explored what’s happening to the mitochondria in people with Parkinson’s without a PINK1 gene change, and now a number of potential treatments are targeting the mitochondria in order to slow or stop symptoms getting worse.

Read about the role of mitochondria in Parkinson’s in our blog. 

Identifying new drugs which target genes

Genetic research in Parkinson’s has significantly advanced the discovery of new drugs by uncovering key genes and mechanisms involved in the development of the condition. 

Drugs which target the GBA1 gene

The GBA1 gene contains instructions to make glucocerebrosidase (GCase). GCase is an enzyme; a specific type of protein that breaks up waste. It’s involved in the waste disposal system inside cells which removes fats and damaged proteins. Changes to the GBA1 gene significantly increases the risk of developing Parkinson’s compared to the general population. But not everyone with a change in the GBA1 gene will go on to be diagnosed with Parkinson’s.

In Parkinson’s, changes to the GBA1 gene reduce the activity of GCase, so cells struggle to remove fats and damaged proteins, including alpha-synuclein. These findings have led to research into drugs which aim to improve the activity of GCase, or boost the waste disposal system of cells. Such as ambroxol, a component of a cough medicine. We’re co-funding a phase 3 clinical trial of ambroxol in people with Parkinson’s, with and without a GBA1 gene change, to see whether it can slow the condition.

Drugs which target the LRRK2 gene

Affecting around 2% of people with Parkinson’s, one of the most common gene changes known to cause Parkinson’s is in the LRRK2 gene.

Changes to the LRRK2 gene can make the LRRK2 protein overactive. This causes a range of problems that disrupt brain cells, including problems with how cells communicate, process waste products and produce the energy that they need to function. These issues lead to the death of dopamine-producing brain cells. Researchers have since discovered that this can also happen in people with Parkinson’s who don’t have a change in their LRRK2 gene.

Now, researchers are developing new drugs which target the LRRK2 protein to help it function normally. Drugs which stop LRRK2 from becoming overactive are in late stage clinical trials in people with and without changes to their LRRK2 gene.

The LITE study at the University of Dundee is carrying out research to understand how LRRK2 works in different groups of people. Find out how to take part on our Take Part Hub.

Subgroups and personalised treatments

Parkinson’s is a complicated condition with over 40 symptoms. No two people experience the condition in the same way. Studying the genetics of such a complex condition may help identify specific subgroups who could then be treated with more effective, personalised treatments.

The Global Parkinson’s Genetic Programme (GP2) aims to study the genetics of 250,000 people with Parkinson’s around the globe, building the world’s largest Parkinson’s genetic dataset. The project aims to uncover what genetic factors are involved, how they interact with the environment, and whether people with Parkinson’s may fit into sub groups. 

The ambitious programme will make sure that people from global majority backgrounds are properly included, so the results represent the whole Parkinson’s community. Genetic research has often focused on people from white, European backgrounds, meaning we’re missing a large piece of the puzzle when it comes to understanding the full picture.

As a charity, we fund research that we know matters to the community. Currently, we’re investing in groundbreaking studies to get to the bottom of how our genes influence Parkinson’s. This knowledge will lay the foundations for new and better treatments.

• At the University of Oxford, Dr Sophie Farrow, one of our Senior Fellows, is leading a study to explore how and why some changes in certain genes can increase a person’s risk of Parkinson’s.

  Sophie shared: “I aim to integrate multiple genomic approaches to identify and prioritise potential drug targets, with the vision to accelerate early-stage drug target selection and repurposing for people with Parkinson’s.”

• Dr Kathryn Bowles at the University of Edinburgh is also investigating genes which could be involved in Parkinson’s. By comparing differences in genes between people with and without Parkinson’s, the team identified that people with Parkinson’s had much fewer copies of a gene called LRRC37A2 than those without the condition. Now, Kathryn will explore how this gene may be involved in Parkinson’s.
• Professor Helene Plun-Favreau at University College London is exploring the role of a gene called LGALS3, which creates a protein called Galectin-3. This small protein is involved in clearing away damaged material in cells, a process which is disrupted in people with Parkinson’s. The team aims to understand how the LGALS3 gene may be linked to Parkinson’s.

We know that not everyone wants to know whether they carry any genetic changes that may increase their risk of Parkinson’s.

When you take part in a research study that involves genetic testing, you will be offered genetic counseling to guide you through the process and results. You can also change your mind at any time during the research process.

These studies are currently looking for people to take part, and involve a blood test which will allow the researchers to look for genetic changes:

• PD Frontline: The aim of the research is to find a large number of people who have small genetic changes in genes such as LRRK2 or GBA1. These people may be invited to take part in future clinical trials of drugs that target these genes. Find out more
• Parkinson’s Families project: This research aims to understand more about the genetics of Parkinson's and other movement disorders, in order to develop better tests and medications that could help slow, stop or prevent Parkinson's. Find out more