Susceptibility to Parkinson’s disease is due to a combination of genetic predisposition, environmental stress factors and the ageing process. There are multiple forms of the disease, but most cases are late onset and “idiopathic”, which means that the initiating cause is not clear. Nevertheless, human genetic research has identified a number of proteins that are particularly important.
Changing the amount or functionality of four different proteins (so far) has been shown to cause Parkinson’s disease.
Alpha synuclein (gene: SNCA or PARK1)). This protein was first linked to Parkinson’s disease by human genetics. Certain rare mutations, including multiple copies, of the gene encoding alpha synuclein were found to cause familial (hereditary) Parkinson’s disease. Alpha synuclein is found at the synapse, the key structure involved in communication between nerve cells. Available evidence indicates that the synapse is where the first pathological changes of the nerve degeneration process occur. Alpha synuclein has taken centre stage recently, based on evidence that Parkinson’s disease spreads from nerve cell to nerve cell, with alpha synuclein the key factor in the process.
Leucine-rich repeat kinase 2 (gene: LRRK2 or PARK8). This protein has attracted considerable interest. Many different mutations in the gene encoding this protein lead to familial (hereditary) Parkinson’s disease, and most notably these are not rare. The frequency of LRRK2 mutations as a cause of Parkinson’s disease varies between human populations, but is typically 3 to 5% of familial cases and up to 3% of “idiopathic” cases, and strikingly up to 40% of cases in certain North African populations and the Ashkenazi Jewish population. Also, the symptoms of LRRK2 Parkinson’s disease are usually indistinguishable from the majority “idiopathic” form of the disease.
The other two proteins in this class are VPS35 (vesicular protein sorting 35 homologue) and EIF4G1 (eukaryotic translation initiation factor 4-gamma 1). Clearly pathogenic mutations have only been found in two and one family respectively.
In contrast, the loss of activity of certain other proteins can cause Parkinson’s disease. Of these, parkin, DJ1 and PINK1 are all associated with mitochondrial function or the removal of damaged mitochondria. Loss of parkin leads to the most common form of very early onset or juvenile Parkinson’s disease, and the loss of one functional allele of parkin may become a risk factor for Parkinson’s disease with increasing age. Other proteins in this class are ATPase type 13A2, phospholipase A2 group VI, F box only protein 7 and neuronal specific clathrin uncoating co-chaperone auxilin.
Many other proteins are involved. Genetic changes that increase the risk of Parkinson’s disease have been identified that affect at least 20 other proteins. Given the complexity of the cellular systems involved – including vesicle trafficking, mitochondrial function and protein and organelle clearance systems – we expect that more will be identified. Among those risk factors that are well established are variants in glucocerebrosidase, which may be involved in removing alpha synuclein, and the tau protein that also plays a role in Alzheimer’s disease.