The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia

Abstract

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

“…In addition, Gly111-Glu114 and Gly132 located in the C-terminal region present abundant 3 10 -helix formation (up to 28%) for both the wild-type and A30 mutant-type αS proteins. We also note a larger decrease in 3 10 -helix abundance (≥5%) at Phe94-Leu100 in the A30P mutant-type structures rather than those of the wild-type αS protein.…”

“…Interestingly, Gly7-Glu13, Val15-Ala17, Lys32-Val40, and Lys43-Gly47 adopt more prominent helical structure (α-helix or 3 10 -helix; up to 30%) in the structures of the A30P mutanttype than in those of the wild-type αS protein. In contrast, the α-helix and 3 10 -helix contents at Gly25-Lys32 in the wild-type αS protein structures decrease or disappear upon A30P mutation. This finding is in agreement with the NMR measurements that reported reduced helical propensity for Ala18-Gly31 upon A30P mutation.…”

“…The helical and β-sheet structure formations have been proposed to play crucial roles in the aggregation process of intrinsically disordered fibrillogenic proteins at the center of neurodegenerative diseases. 12,14,24,41 Within the N-terminal region (Met1-Lys60) of the wild-type and A30P mutant-type αS, we detect abundant α-helix formation at Ala19-Lys23 and 3 10 -helix formation at Val15-Ala18, Glu20-Thr22, Gly41-Thr44, and Thr54-Lys60 varying between 20% and 35% ( Figure 1). Interestingly, Gly7-Glu13, Val15-Ala17, Lys32-Val40, and Lys43-Gly47 adopt more prominent helical structure (α-helix or 3 10 -helix; up to 30%) in the structures of the A30P mutanttype than in those of the wild-type αS protein.…”

“…Furthermore, the variations in the secondary and tertiary structures as well as free energy landscapes were not presented in these earlier studies. Annealing molecular dynamics simulations by Balesh et al presented a decrease in α-helix structure in the A30P mutant-type αS protein structures but an increase in the 3 10 -helix abundance and no change in the β-sheet structure formation upon A30P mutation of the wild-type αS. 35 Detailed information about the tertiary structure and conformational free energy landscape differences was not reported.…”

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

“…Mis‐sense mutations13, 36, 37, 38, 39, 40 and duplications or triplications of the SNCA gene, which encodes αS, lead to autosomal dominant early onset PD 41, 42. It has previously been shown that the formation of αS oligomers in vitro is concentration dependent,12 and ADPAINT now enables us to determine whether this dependence is reflected in cellular models that overexpress αS.…”