LRRK2: A gene behind brain inflammation in Parkinson's disease

For almost twelve years, the researchers searched for the gene mutation that triggered Parkinson's disease in an Asian family in which almost all members were affected. They laboriously trawled through the genes until they finally found the responsible gene around 2008: LRRK2 (pronounced ‘Lark 2’). Mutations in this gene cause the metabolism in brain cells to be dysregulated. Today, LRRK2 is considered a promising target for Parkinson's drugs, although these have yet to be tested.

LRRK2 is a so-called kinase - an enzyme that can activate or deactivate other molecules. One of the tasks of LRRK2 is to regulate the lysosomes, which are responsible for the breakdown of cellular waste. This becomes a problem when LRRK2 turns hyperactive due to mutations in the gene: It then blocks the lysosomes and thus paralyses important transport processes in the brain cells. This results in the physical symptoms typical for Parkinson's disease. For this reason, another name for LRRK2 is dardarin - derived from the Basque word dardara, which means ‘trembling’. 

Clinical studies are focussing on slowing down LRRK2

The particularity of Parkinson's is the heterogeneity of the disease: it can be caused by various triggers, each of which results in a different clinical form. The LRRK2 variant of Parkinson's is characterised by the fact that it mainly occurs in familial Parkinson's cases. More rarely, it occurs in the sporadic form of Parkinson's disease. It is important to note that the familial form of Parkinson's only accounts for around ten per cent of cases, while 90 per cent of patients have the sporadic form. However, the mechanisms at work in the body are similar according to research findings to date, meaning that future therapies targeting an LRRK2 mutation are likely to be effective in a relevant group of patients.

Research is currently working on so-called kinase inhibitors - active substances that suppress LRRK2. This prevents hyperactivity and thus restores the balance within the nerve cells. Such active substances have not yet been approved, but clinical trials are currently underway. 

LRRK2 mutations trigger different clinical pictures

Parkinson's can generally cause very different symptoms, from the well-known tremor to dementia. In the case of the LRRK2 gene, numerous different mutations are known. What is special about this is that the symptoms vary depending on the section of the gene in which the mutation occurs - even within a family where several members have Parkinson's disease, the symptoms vary: Depending on the type of mutation, the disease causes different pathologies.

The fact that inflammatory reactions occur is a particular characteristic of LRRK2 mutations. They are suspected of not only triggering inflammation in the brain - so-called neuro-inflammation -, but also of being responsible for a certain chronic intestinal inflammation. Furthermore, there is another striking connection: LRRK2 also plays a major role in nerve inflammation outside the brain. And these inflammations in turn frequently occur in patients with the sporadic form of Parkinson's disease. This is a further indication that the LRRK2 mutations play a key role in the disease.