Parkinson disease: α-synuclein mutational screening and new clinical insight into the p.E46K mutation

Pimentel, Márcia Mattos Gonçalves; Rodrigues, Fabíola C.; Leite, Marco Antônio Araújo; Júnior, Mário Campos; Rosso, Ana Lucia; Nicaretta, Denise Hack; Pereira, Joäo Santos; Silva, Delson José; Coletta, Marcus Vinicius Della; Vasconcellos, Luiz Felipe Rocha; Abreu, Gabriella M.; Santos, J. M.; Santos-Rebouças, Cíntia Barros

doi:10.1016/j.parkreldis.2015.03.011

Cited by 18 publications

(7 citation statements)

References 30 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The aggregation of α-synuclein (aSyn) plays a central role in the pathogenesis of synucleinopathies like Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) or Multiple System Atrophy (MSA). Point mutations, duplications, and triplications of SNCA , the gene encoding aSyn, lead to familial forms of PD. − So far, six missense mutations in the coding region of SNCA have been identified in families with autosomal dominant forms of PD: A30P, E46K, , H50Q, , G51D, , A53E, , and A53T . Additionally, two variants of unclear significance, A18T and A29S, and very recently, a homozygous A53V mutation have been described. , Clinically, patients with SNCA mutations develop progressive parkinsonism, however, with marked differences in terms of age of onset and clinical presentation of attendant symptoms (Table ): While parkinsonian symptoms in patients with A30P, E46K, and H50Q mutations manifest at higher ages, ,, carriers of the A53T, G51D, or A53E mutation manifest at younger ages (early onset PD). ,,, Patients with the A53T mutation often display signs of associated cognitive impairment and dementia, , whereas patients with the E46K or G51D mutation frequently present with visual hallucinations, ,,, similar to Dementia with Lewy Bodies (DLB).…”

Section: Introductionmentioning

confidence: 99%

“…Point mutations, duplications, and triplications of SNCA, the gene encoding aSyn, lead to familial forms of PD. 1−3 So far, six missense mutations in the coding region of SNCA have been identified in families with autosomal dominant forms of PD: A30P, 4 E46K, 5,6 H50Q, 7,8 G51D, 9,10 A53E, 11,12 and A53T. 13 Additionally, two variants of unclear significance, A18T and A29S, and very recently, a homozygous A53V mutation have been described.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Different Effects of α-Synuclein Mutants on Lipid Binding and Aggregation Detected by Single Molecule Fluorescence Spectroscopy and ThT Fluorescence-Based Measurements

Ruf

Nübling

Willikens

et al. 2019

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Six α-synuclein (aSyn) point mutations are currently known to be associated with familial parkinsonism: A30P, E46K, H50Q, G51D, A53E, and A53T. We performed a comprehensive in vitro analysis to study the impact of all aSyn mutations on lipid binding and aggregation behavior. Markedly reduced lipid binding of A30P, moderately attenuated binding of G51D, and only very slightly reduced binding for the other mutants were observed. A30P was particularly prone to form metal ion induced oligomers, whereas A53T exhibited only weak tendencies to form oligomers. In turn, fibril formation occurred rapidly in H50Q, G51D, and A53T, but only slowly in A30P, suggesting mutants prone to form oligomers tend to form fibrils to a lesser extent. This was supported by the observation that fibril formation of wild type aSyn, A30P, and A53T was impaired in the presence of ferric iron. Additionally, we found the aggregation kinetics of mixtures of A30P or A53T and wt aSyn to be determined by the faster aggregating aSyn variant. Our results implicate differential mechanisms playing a role in aSyn pathology on the molecular level. This might contribute to a better understanding of Parkinson’s disease pathogenesis and provide potential links to develop prevention strategies and disease-modifying therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Different Effects of α-Synuclein Mutants on Lipid Binding and Aggregation Detected by Single Molecule Fluorescence Spectroscopy and ThT Fluorescence-Based Measurements

Ruf

Nübling

Willikens

et al. 2019

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Interestingly, visual hallucinations and autonomic dysfunction were also manifested in G51D cases with variable AAO and pyramidal signs 13,35 . SNCA E46K mutation was first reported in a family of Spanish origin, with severe parkinsonism and dementia with Lewy bodies (DLB) 10 and then it was found in a Bolivian family with a less aggressive phenotype and without dementia, 11 which indicated phenotypic heterogeneity in PD patients with the same mutation. The A53E mutation in SNCA results in hypokinetic‐rigid PD with early‐onset (AAO, 34.3 ± 8.6 years), prominent levodopa‐induced dyskinesia, but without cognitive decline 15 .…”

Section: Discussionmentioning

confidence: 99%

“…The A53V mutation was found in one dominant Japanese family but in a homozygous state 8 and in one dominant family and two sporadic PD cases from China in a heterozygous state, 9 but it still needs more functional or pathological evidence to confirm whether homozygous or heterozygous A53V mutation can predispose carriers to PD. Other SNCA missense mutations (E46K, 10,11 G51D, 12,13 and A53E 14,15 ) have been found in several families and/or cases, while A30P was only found to co‐segregate in five affected cases of one German family 16 …”

mentioning

confidence: 99%

A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease

et al. 2021

View full text Add to dashboard Cite

A BS TRACT: Background: The SNCA gene encoding α-synuclein (αSyn) is the first gene identified to cause autosomal-dominant Parkinsonʼs disease (PD). Objective: We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences. Methods: Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.Results: We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co-segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation. Conclusion:Based on the identification of A30G cosegregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD.

show abstract

“…However, the severe weakness due to the co-existing severe HMSN2 may have made it difficult to appreciate possible subtle signs of parkinsonism. Reduced penetrance has been extensively reported, especially for SNCA duplications but also in missense variants, while SNCA triplications appear to be more penetrant [7,[17][18][19][20][21][22]. The reasons for this incomplete penetrance and variable expressivity remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

Fevga

Park

Lohmann

et al. 2021

Parkinsonism & Related Disorders

View full text Add to dashboard Cite

Introduction: Missense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD). Methods: Two families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein.Results: We identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer. Conclusion:We present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.

show abstract

Parkinson disease: α-synuclein mutational screening and new clinical insight into the p.E46K mutation

Cited by 18 publications

References 30 publications

Different Effects of α-Synuclein Mutants on Lipid Binding and Aggregation Detected by Single Molecule Fluorescence Spectroscopy and ThT Fluorescence-Based Measurements

Different Effects of α-Synuclein Mutants on Lipid Binding and Aggregation Detected by Single Molecule Fluorescence Spectroscopy and ThT Fluorescence-Based Measurements

A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease

A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

Contact Info

Product

Resources

About