Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

Meeus, Bram; Nuytemans, Karen; Crosiers, David; Engelborghs, Sebastiaan; Peeters, Karin; Mattheijssens, Maria; Elinck, Ellen; Corsmit, Ellen; Deyn, Peter Paul De; Broeckhoven, Christine Van; Theuns, Jessie

doi:10.3233/jad-2010-1356

Cited by 20 publications

(9 citation statements)

References 37 publications

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“…In-depth molecular genetic follow-up investigations, including comprehensive sequencing of all positional candidate genes and high-resolution copy number variation analyses, did not reveal a simple pathogenic or gene dosage mutation that cosegregated with DLB in this pedigree. 17 Most likely, the mutation underlying DLB in this family is more complex than what is usually envisaged for monogenic disorders.…”

Section: Molecular Genetics Of Dlbmentioning

confidence: 92%

The Genetics of Dementia With Lewy Bodies

Meeus¹,

Theuns²,

Broeckhoven³

2012

Arch Neurol

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ementia with Lewy bodies is a complex brain disorder and a key member of the Lewy body disease spectrum. Its genetic etiology is unclear, and information is scattered. However, the results of molecular genetic studies imply a genetic and mechanistic overlap with Alzheimer disease, Parkinson disease with dementia, and Parkinson disease. In this review, we provide a comprehensive overview of the current studies on dementia with Lewy bodies heritability, genetic etiology, and genetic heterogeneity. We conclude with a critical discussion of the missing heritability in dementia with Lewy bodies and encourage scientists to further explore the underlying mechanisms of this disease.

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Section: Molecular Genetics Of Dlbmentioning

confidence: 92%

The Genetics of Dementia With Lewy Bodies

Meeus¹,

Theuns²,

Broeckhoven³

2012

Arch Neurol

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“…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].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…In the past few years, mutations have been identified in the genes encoding alpha‐synuclein,41–43 leucine‐rich repeat kinase 2,44 and glucocerebrosidase45 in some patients with DLB. Furthermore, a novel locus for familial DLB has been mapped to chromosome 2q35–q36 46. Collectively, these discoveries highlight a substantial overlap between the known genetic determinants of PD and DLB, as well as the presence of profound etiologic heterogeneity in Lewy body disorders.…”

Section: Advances In the Past 25 Yearsmentioning

confidence: 97%

Milestones in atypical and secondary Parkinsonisms

2011

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During the last decades, atypical parkinsonian disorders such as multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration along with secondary parkinsonian disorders have been increasingly recognized as important causes of parkinsonism. Although treatment options are largely limited to date, remarkable progress has occurred through advances in the fields of molecular biology and diagnostic neuroimaging, resulting in intense preclinical drug discovery programs. Early-investigation-assisted clinical diagnosis has become more crucial than ever because disease-modifying therapies will hopefully become available within this decade.

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Comprehensive Genetic and Mutation Analysis of Familial Dementia with Lewy Bodies Linked to 2q35-q36

Cited by 20 publications

References 37 publications

The Genetics of Dementia With Lewy Bodies

The Genetics of Dementia With Lewy Bodies

The role of α-synuclein in neurodegeneration — An update

Milestones in atypical and secondary Parkinsonisms

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