Genetics in Parkinson's

Although a clear direct inheritance pattern is very rarely seen in Parkinson’s (PD), directing research into its genetic underpinnings is strongly supported by the invaluable insights this yields into the molecular pathways that underlie it. Approximately 20% of people with Parkinson’s report an affected first or second degree relative, but because many of the genes involved are often only partially expressed, deciphering a clear pattern is complex. Pinpointing the key genetic players is essential because it helps us understand the underlying disturbed physiological processes associated with the disease, which in turns aids in developing targeted disease-modifying treatments. Here we outline four major candidates that have contributed to this process, although it is important to acknowledge that many more genes are involved: some mutations are rare but have large effects while others are relatively more common and have smaller effects.

Alpha synuclein is a protein which is found under normal conditions within neurons, and is involved in numerous processes of neuronal communication and transmission. In PD, mutations and multiplications in the SNCA gene that codes for it cause alpha synuclein to build up and undergo misfolding into harmful aggregates inside cells. These alterations in SNCA cause familial PD with symptom load generally increasing with an increasing number of multiplications (that is, repetitions of the original DNA sequence that defines the gene). Moreover, we now know that in addition to changes within the SNCA gene itself, changes in the DNA strand around it can also lead to abnormalities in alpha synuclein seen in 'idiopathic' PD - where there is no known cause. Misfolded alpha synuclein has the ability to spread to healthy neurons and trigger further misfolding cascades.

Cellular waste clearance processes, collectively referred to as autophagy, which amongst other processes remove misfolded alpha synuclein from cells are therefore key. Glucocerebrosidase (GCase) is a lipid handling enzyme which is centrally involved in lysosomal clearance mechanisms. Mutations in the GBA gene are therefore the most frequently seen genetic risk factor for PD, due to their adverse effects on autophagy and the build-up of alpha-synuclein.

Mutations in the gene that codes for the leucine-rich repeat kinase 2 or the LRRK2 gene are a major cause of familial and sporadic (non-familial) PD. Up to fifty different mutations have been identified, and in certain populations, such as in North Africa, they can account for up to a third of all PD cases. LRRK2 is a complex protein, a part of which acts as an enzyme catalyst or kinase and interacts with a number of other mediators of cellular signalling. Gene mutations lead to a toxic upregulation or increased response of this enzyme, with multiple detrimental knock-on effects.

PTEN-induced putative kinase 1 or PINK1  is another enzyme which is thought to be neuroprotective. Under normal conditions, PINK1 is involved in mitophagy, the appropriate cellular 'labelling' and targeting of dysfunctional mitochondria for degradation. PINK1 recruits another protein, PARKIN, which is coded by the PARK2 gene, which in turn instigates their appropriate breakdown. Mutations in either or both of these genes interfere with cellular metabolism leading eventually to dopaminergic cell loss and early onset Parkinson’s.

Ongoing efforts into disease modification are focusing on molecular targets, many of which stem from identifying these genes, and others, which are involved in different forms of Parkinson’s. No single gene mutation definitively causes Parkinson's, as even the autosomal dominant mutations in SNCA, GBA and LRRK2 are characterised by only partial penetrance, manifesting into tangible dysfunction in only a proportion of carriers. Nonetheless, research into these multiple, potentially interacting genetic culprits is continually contributing to mapping the different disease processes underlying different forms of Parkinson’s.

Another unanswered question is whether these genetic mutations can influence the outcome of the condition? Do these genetic alterations affect how fast or slow a person's Parkinson's can progress?

This question has recently been investigated by a large consortium of researchers (including Professor Roger Barker who sits on The Cure Parkinson's Trust's Linked Clinical Trials committee). The researchers analysed 31 known risk factors for Parkinson's and looked to see if any of these influenced the course of the condition using clinical measures of disease progression that had been collected over time. To do this, they assessed both the genetic and longitudinal clinical evaluation data from a total of 4,307 people with Parkinson's who attended research in Europe, North America and Australia. The collected data represented 23,423 visits from 13 longitudinal research cohorts.

The results found that several genetic risk factors (such as GBA and LRRK2) are associated with affecting the progression of Parkinson's. The researchers acknowledge that there is a lot of variability within their data, but this type of analysis and data could have important implications for the work that CPT is doing, particularly in regard to our Linked Clinical Trials. For example, in future trials we may need to balance the participants enrolled in a trial based on their genetic variations so that one treatment group is not biased by individuals with or without these genetic factors that could in turn affect the outcome.

Dr Simon Stott said:

The genetics of Parkinson's is very complicated and it is important for everyone to understand that these variations in our DNA are simply associated with an increased risk of developing the condition. Just because an individual has a genetic risk factor for developing Parkinson's does not mean that they will. There is no definitive genetic test, but work like the study described above is helping us to better understand how our DNA is influencing the condition.

Participation in genetic studies and sharing genetic data by people with Parkinson’s and their families is therefore essential to ensuring progress towards cures.

Want to find out more? Read 'Too much LRRK2 begets too little GCase?' by Deputy Director of Research Dr Simon Stott

Also... 'The genetics of Parkinson's - new mutants' by The Science of Parkinson's