Genetics of Parkinson disease

Abstract

During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease. Thus, researchers have continued to search for genes that may influence disease susceptibility. Molecular diagnostic testing is currently available for four of the genes mutated in Parkinson disease. Evidence for reduced penetrance, possible effects of haploinsufficiency, and the identification of nondisease causing polymorphisms within several of these genes has made genetic counseling challenging.Current recommendations are to limit molecular testing only to those individuals who are symptomatic. Furthermore, because treatment is unaltered by the presence or absence of mutations in these genes, restraint is recommended when considering the value of screening for mutations in a clinical setting. Genet Med 2007:9(12): 801-811.

The leucine rich repeat kinase 2 (LRRK2) G2019S substitution mutation

“…Mutations in the α synuclein (SNCA; MIM #163890), leucine rich repeat kinase 2 (LRRK2 MIM #609007), and ubiquitin carboxyterminal hydrolase L1 (UCHL1 MIM #191342) genes cause autosomal-dominant forms, whereas mutations in the parkin (MIM #602544), DJ-1 (MIM #602533) and phosphatase and tensin (PTEN)-induced kinase1 (PINK1) (MIM #608309) genes cause autosomal recessive forms. Mutations in most of these genes are generally rare, even in familial cases (except for Parkin mutations, which are a common cause of early onset PD) and have been considered even rarer in classic, late-onset PD [22]. Nearly a dozen different mutations have been reported in the most recently identified PD predisposition gene, LRRK2 [21,24].…”

“…Rarely, PD is inherited as a Mendelian trait, with either autosomal-dominant or -recessive inheritance [22]. At the time of writing, 11 genomic loci and 6 genes have been reported to be associated with the familial forms of PD.…”

Generation of Reactive Oxygen Species by Mitochondrial Complex I: Implications in Neurodegeneration

“…To this purpose, mtDNA mutations may be involved in the aetiology and predisposition to the idiopathic disease, since cybrids containing mitochondria from Parkinson's patients exhibit a reduced activity of Complex I [180] and generate Lewy inclusion bodies [181]. However, exhaustive sequencing of mtDNA has not yet revealed mutations that consistently associate with PD [182]; nevertheless, somatic deletions of mtDNA are found more frequently in SN from PD patients [183,184].…”

The Potential of Proteomics in Understanding Neurodegeneration

“…The main characteristic of PD is the loss of dopaminergic neurons in the substantia nigra and formation of Lewy bodies enriched in the protein α-synuclein (SNCA) (Martin et al, 2012). Although the majority of PD cases are sporadic and age-related, mutations in several genes have been identified in early-onset familial forms of PD including SNCA, Parkin (PARK2), ubiquitin carboxyl-terminal esterase L1 (UCHL1), Parkinson protein 7 (PARK7, DJ-1), PTEN-induced putative kinase 1 (PINK1), leucine-rich repeat kinase 2 (LRRK2), SNCA-interacting protein (SNCAIP), and β-glucocerebrosidase (GBA) (Pankratz & Foroud, 2007).…”