Parkinson disease is a multifactorial neurodegenerative disorder. It can be either familial or sporadic.7 In the majority of cases, Parkinson disease occurs due to sporadic causes resulting from the interplay of both genetic mutations and environmental exposures.7 While the nature of the genetic involvement in PD requires further research, it is well recognized as having considerable involvement in the onset, progression, and clinical symptoms of the disease.1 , 31 Whether familial or sporadic, the same pattern of dopaminergic neuron degeneration in the substantia nigra occurs.31
Currently, 26 genetic variations and gene loci have been identified as contributing to the risk of Parkinson disease.32 Of these, there are six known monogenic forms of PD, accounting for 3 to 5% of sporadic and 30% of familial cases.1 , 20 Inheritance follows both autosomal-dominant and autosomal-recessive patterns. The scope of research into these monogenic mutations and their relationship to Parkinson disease is outlined below.
There are currently three genes associated with autosomal-dominant monogenic forms of Parkinson disease: SNCA, LRRK2, and VPS35.32
The first gene linked to PD was that of SNCA: a 140-amino acid protein encoding for α-synuclein. As mentioned above, mutations in this gene include point, duplications, and triplications, and follow an autosomal-dominant pattern of inheritance. Mutated SNCA produces a form of α-synuclein that is misfolded, insoluble, and contributes to PD pathogenesis by aggregating in the cell bodies and processes of neurons as inclusions, forming a substantial component of Lewy bodies and neurites, respectively.7 On its own, α-synuclein does not produce such effects but is toxic in these excess aggregations.7 , 33
A hallmark characteristic in the progression of Parkinson disease is an accumulation of aggregated α-synuclein and the resulting Lewy body pathology. This follows specific patterns as the disease progresses.34 The SNCA mutation itself causes an early onset, rapidly progressing form of Parkinson disease, which has been associated with both familial and sporadic cases.1
The most common genetic mutation in Parkinson disease occurs in leucine-rich repeat kinase 2 (LRRK2), which accounts for 1% of sporadic and 4% of familial occurrences.7 This mutation results in a form of the disease with the mid-late onset and slow progression.7 The LRRK2 protein is involved in “neurite outgrowth, synaptic morphogenesis, membrane trafficking, autophagy and protein synthesis.”7 Eight mutations of LRRK2 have been linked to PD, with the Gly2019Ser substitution being the most common.7 LRRK2-induced Parkinson disease is highly prevalent in North African Arab and Ashkenazi Jew ethnic groups, accounting for 30% of familial, 13% of sporadic and 37% of familial, and 41% of sporadic cases, respectively.7
The final monogenic form of PD inherited through autosomal-dominant patterns is VPS35 (vacuolar protein sorting 35 retromolar complex). This protein is responsible for transporting proteins between endosomes and the Golgi apparatus.32 It causes late-onset PD.