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. Glucocerebrocidase 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 (LRRK2) 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 (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.

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