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 α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐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 α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.
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All known autosomal dominant point mutations that cause PD reside within the 11-residue repeat motifs of αSyn.
“all known autosomal dominant point mutations that cause PD reside within these repeat motifs, specifically A30P[120], E46K[121], A53T[122], G51D[123], and H50Q[124]”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [121]
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- Authors
- Zarranz, J. J., Alegre, J., Gómez‐Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atarés, B., Llorens, V., Tortosa, E. G., del Ser, T., Muñoz, D. G., & de Yebenes, J. G.
- Affiliations
- University of the Basque Country (ES)
- Hospital Txagorritxu (ES)
- Hospital de Cruces (ES)
- Corresponding author
- Zarranz, Juan J.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2003-12-30
- Volume
- 55
- Issue
- 2
- Pages
- 164-173
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W1965778124
- Cited by
- 2,737
- References
- 53
- Citations by year
- 2026: 54 · 2025: 88 · 2024: 116 · 2023: 109 · 2022: 115 · 2021: 109 · 2020: 115 · 2019: 129 · 2018: 127 · 2017: 136 · 2016: 108 · 2015: 125 · 2014: 132 · 2013: 156 · 2012: 142
- FWCI
- 58.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Progressive Supranuclear Palsy Society (06.2001)
- Fundación Areces (03-2000)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, E46K mutation, familial parkinsonism, dementia with Lewy bodies, Lewy bodies, autosomal dominant inheritance, visual hallucinations, synucleinopathies, novel mutations
- MeSH terms
- Aged, Amino Acid Sequence, Base Sequence, Brain, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Male, Middle Aged, Molecular Sequence Data, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Parkinson Disease, Pedigree, Tomography, Emission-Computed, Single-Photon, Polymerase Chain Reaction, Lewy Bodies, Sequence Homology, DNA Primers, Lewy Body Disease, Synucleins, alpha-Synuclein
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