Expansion of the Parkinson disease-associated SNCA- Rep1 allele upregulates human α-synuclein in transgenic mouse brain

Abstract

α-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.

Acid β‐glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter α‐synuclein processing

“…Graph is substantially modified from earlier versions (in Tomlinson et al 40 and Klein et al 43 ). *Data inferred from mouse studies on the Rep1 allele expansion effect on enhanced SNCA transcription 28 and the effect of GBA1 mutations in this report (ie, mean rise by 10-24%; see Fig 3; red circle). N.D. 5 not determined.…”

Genome-wide association study confirms extant PD risk loci among the Dutch

“…26,28,38,39, Gene expression differences caused by this repeat have also been described both in vitro 35,40 and in vivo. 41,42 We agree that examining this microsatellite in our population would help understanding whether the effect detected on the 5¢ block is a residual effect of variation in REP1 caused by LD between the associated alleles. However, these experiments could not be performed because only genotypic information was available for the control population used in this study.…”

The role of α-synuclein in neurodegeneration — An update

“…However, only the AS species with increased aggregating propensities, human WT and A30P, triggered degeneration of nigral DAergic neurons, suggesting that fibril formation of AS promotes the progressive neuronal degeneration [314]. Expansion of Rep1, a polymorphic mixed-dinucleotide repeat in the SNAC promoter region that increases expression in both animal models [315] and humans [316], is associated with elevated risk of sPD [317,318], while short Rep1 genotype is associated with reduced PD risk [319][320][321][322][323][324], but the effect of SNCA variants on the predisposition of PD is independent of Rep1 [325]. Variants of all 3 members of the Syn family, particularly SA and SG, affect the risk of developing DLBD [326], and detection of a gene for familial DLB in 2q35.q36 emphasized its genetic heterogeneity [327,328].…”