Causes of Parkinson's disease
Most people with Parkinson's disease have idiopathic Parkinson's disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors such as environmental toxins, herbicides, pesticides, and fungicides, have been associated with the risk of developing PD, but no causal relationships have been proven.
PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease. At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.
Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2. In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD. The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease. Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results. Mendelian genetics are not strictly observed in GBA mutations found in inherited parkinsonism. Incidentally, both gain-of-function and loss-of-function GBA mutations are proposed to contribute to parkinsonism through effects such as increased alpha-synuclein levels.
The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies. SNCA is expressed throughout the mammalian brain and enriched in presynaptic nerve terminals. Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD. Missense mutations in SNCA are rare. On the other hand, multiplications of the SNCA locus account for around 2% of familial cases. Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent. Level of alpha-synuclein expression correlates with disease onset and progression, with SNCA gene triplication advancing earlier and faster than duplication.
The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain. Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number. Mutations in PINK1, PRKN, and DJ-1 may cause mitochondrial dysfunction, an element of both idiopathic and genetic PD. Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia. This could be relevant in PD cases associated with dementia.
|Locus||Gene||Function||Mutations||Clinical Presentations||Neuropathology||Age at onset||Inheritance|
|PARK1/PARK4||SNCA (α-synuclein)||Unknown synaptic function||Duplications||Idiopathic PD; some postural tremor; slow progression||LBs||Mid 20 - 30||Dominant|
|Triplications||PD (Parkinson's Disease); PD with dementia;diffuse LBs disease;aggressive course||LBs and Lewy neurites; ± glial inclusions; hippocampal CA2 and CA3 loss||Mid 20's - 30's|
|A53T, A30P E46K||Idiopathic PD; early on setparkinsonism and diffuse LBs||LBs and LNs; ± tau inclusions; amyloid plaques||30 - 60|
|PARK2||Parkin||E3 ubiquitin ligase||200+ possible mutations including:
- Inactivating somatic mutations
- Frequent intragenic deletions
|Early on set Parkinsonism; slow progression PD||variable presence of LBs||Juvenile to 40||Recessive|
|PARK5||UCHL1||deubiquitinating enzyme||Missense: Ile93Met ||PD; late on set parkinsonism||Unknown; various abnormal protein aggregations||30 - 50||Dominant|
|PARK6||PINK1||mitochondrial Ser-Thr Kinase||40+ mutations
-Mostly point mutations
-Deletions on C-terminus Kinase domain
|Parkinsonism||Unknown||30 - 50||Recessive|
|PARK7||DJ-1||oxidative stress response?||-10 point mutations including C46A, C53A, C106 & WT regions
- Large deletion in L166P
|Early onset Parkinsonism||Unknown||20 - 40||Recessive|
|PARK8||LRRK2 (dardarin)||unknown protein kinase||G2019S most common ||PD||Diffuse LBs; LNs; ± tau inclusions; ± amyloid plaques||40 - 60||Dominant|
PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated
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