Genetic Basis of Monogenic Forms of Parkinson Disease


There has been a plethora of genetic findings in Parkinson's disease (PD) during the last decade, and mutations in an increasing number of genes are found to cause monogenic forms of this disorder. To date, we know of 15 gene loci (PARK1–15) causing either autosomal dominantly or autosomal recessively inherited forms of PD. Proteins encoded by PD‐associated genes play important roles in different cellular functions and partially interact with each other suggesting that they share common pathways that lead to neuronal degeneration. At least some of these genes may also play a direct role in the aetiology of sporadic PD, and therefore it seems likely that the cellular pathways identified in familial variants of the disorder also elucidate the molecular pathogenesis in the sporadic form.

Recently, these genetic findings have begun to impact clinical practice. Here, we highlight these genetic advances, and discuss their importance for clinical practice.

Key Concepts:

  • Since both, monogenic and sporadic forms of PD, tend to share many overlapping features that include, most importantly, parkinsonism with nigrostriatal dopaminergic degeneration genetic findings imply common pathogenic mechanisms and may provide new insights in the specific molecular pathways underlying PD.

  • Since α‐synuclein was found to be the major component of Lewy bodies in familial and sporadic cases aggregation of this protein is thought to be a crucial step in dopaminergic neurodegeneration in both, SNCA‐linked as well as sporadic PD.

  • LRRK2 represents the most frequent form of autosomal dominantly inherited late‐onset PD offering the possibility to study the development of the disease in a sizeable population.

  • Presumption is rising that parkin, PINK1 and DJ‐1 which are associated with autosomal recessive forms of PD may act in a common pathway and that mutations within one of these genes imply ‘loss‐of‐function mechanism’ leading to cell death underlying mitochondrial and proteasomal dysfunction.

  • Longitudinal studies in presymptomatic mutation carriers may reveal pre‐motor changes by clinical, biochemical or imaging methods, indicating the very early phases of neurodegeneration. Therefore, further research in this population exploring neuroprotective or preventive measures are most promising to yield first results.

Keywords: PARK; SNCA; LRRK2; parkin; PINK1; DJ1

Figure 1.

Prevalence of LRRK2 mutations within the PD populations. The G2019S mutation is found in 30% of PD patients from North African and Ashkenazi Jews origin whereas in China the G2385R mutation is recognized in 8% of the PD patients. An increased prevalence of LRRK2 mutations in general is noticed in Southern Europe (7%) compared to the Northern part of Europe (2%).

Figure 2.

Schematic depiction of multiple pathways leading to neuronal death in Parkinson disease. Point mutations in the SNCA gene as well as overexpression of the wild‐type SNCA in familial PD, and potentially mishandling in sporadic PD leads to α‐synuclein oligomerization and aggregation, which may damage multiple essential cellular processes. α‐Synuclein is the major fibrillar component of Lewy bodies and Lewy neurites in neurons representing the pathological hallmark of PD. The disease‐relevant function of LRRK2 is still poorly understood. The mutated protein might cause mishandling of α‐synuclein, or disturb essential cellular functions, which might lead to accumulation of α‐synuclein aggregates. Loss of PRKN, PINK1 and DJ‐1 function due to mutations in the corresponding genes results in mitochondrial as well as proteasomal and lysosomal dysfunction and further impairs protein degradation, which may enhance deleterious actions of α‐synuclein oligomers.



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Further Reading

Gupta A, Dawson VL and Dawson TM (2008) What causes cell death in Parkinson's disease? Annals of Neurology 64(suppl. 2): S3–S15.

Hattori N, Shimura H, Kubo S et al. (2000) Importance of familial Parkinson's disease and parkinsonism to the understanding of nigral degeneration in sporadic Parkinson's disease. Journal of Neural Transmission 60(suppl.): 85–100.

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Brockmann, Kathrin, and Gasser, Thomas(Apr 2010) Genetic Basis of Monogenic Forms of Parkinson Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022397]