Parkinsonism due to A53E α‐synuclein gene mutation: Clinical, genetic, epigenetic, and biochemical features

Abstract

Background SNCA mutations cause autosomal dominant parkinsonism and inform our understanding of the molecular underpinnings of synucleinopathies. The most recently identified mutation, p.Ala53Glu (A53E), has only been observed in Finland. The objectives of this study were to examine clinical, genetic, epigenetic, and biochemical features of the first family outside Finland with A53E. Methods We examined a Canadian family with parkinsonism because of A53E using haplotype and DNA methylation analyses. We assessed aggregation properties of A53E α‐synuclein in vitro. Results Family members with parkinsonism shared a common haplotype distinct from Finnish patients with A53E. Increased acceleration of DNA methylation age was accompanied by earlier age at onset in the family members. We demonstrate that A53E α‐synuclein has a propensity to form oligomers and phosphorylation promotes fibrillation. Conclusions A53E as a cause of parkinsonism is not restricted to Finnish individuals. DNA methylation may contribute to disease age at onset. A53E enriches α‐synuclein oligomers and fibrils dependent on the phosphorylation state. © 2018 International Parkinson and Movement Disorder Society

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

“…16 Furthermore, investigation of a PD family with the p.A53E mutation in α-synuclein showed that an earlier onset was accompanied by increased DNAm-age acceleration. 74 Of note, the association between DNAm-age measures and disease traits may depend on the selected DNAm clock. In a study of multiple sclerosis, accelerated phenotypic aging was observed using DNAm PhenoAge, whereas the measures of the Horvath or Hannum clock did not differ from chronological age, 51 which likely reflects the different aging mechanisms behind each DNAm clock.…”

Protein Quality Control Pathways at the Crossroad of Synucleinopathies

“…Two types of mutations in the SNCA gene have been linked to autosomal dominant forms of PD, highlighting distinct mechanisms by which ␣-Syn aggregation can be triggered: (i) increased gene dosage and (ii) point mutations enhancing ␣-Syn aggregation propensity. The latter, including A30P [37], E46K [38], H50Q [39,40], G51D [41], and A53T [42], A53V [43], and A53E [44] (see Fig. 1), have been discovered by genetic screens in families with hereditary PD and directly influence ␣-Syn aggregation to different extents and via discrete pathways [45].…”

Synuclein alpha accumulation mediates podocyte injury in Fabry nephropathy

“…SNCA is highly produced in many cells and constantly degraded through chaperone-mediated autophagy (39). This protein has been implicated in other lysosomal storage diseases (40) and is well-known in synucleinopathy related neurodegenerative diseases such as Parkinson disease (41,42). Importantly, the aggregation of pathological SNCA isoforms has been reported as toxic to cells (43)(44)(45), and the modulation of SNCA-signalling reverses lysosomal clustering (46), suggesting that SNCA may be an intriguing therapeutic target for FD (47).…”