Genetic Component of Parkinson Disease

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.

Autosomal-Dominant Mutations

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.

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