α-synuclein locus duplication as a cause of familial Parkinson's disease

Chartier-Harlin, Marie-Christine; Kachergus, Jennifer M.; Roumier, Christophe; Mouroux, Vincent; Douay, X.; Lincoln, Sarah; Lévecque, Clotilde; Larvor, Lydie; Andrieux, Joris; Hulihan, Mary M.; Waucquier, N.; Defebvre, Luc; Amouyel, Philippe; Farrer, Matthew J.; Destée, Alain

doi:10.1016/s0140-6736(04)17103-1

Cited by 1,847 publications

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“…In a family with early-onset autosomal dominant PD and dementia, the disease segregated with a triplication of a genomic region containing 17 genes (initially referred to as the PARK4 locus), one of which was the α-Synuclein gene [181]. Subsequently, several other PD families both with duplications and triplications including the α-Synuclein locus were described in different populations [192][193][194][195]. A Swedish/American family showed a duplication in the Swedish branch and a triplication in the American branch [193].…”

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confidence: 99%

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Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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confidence: 99%

“…The severity of the phenotype seems to be related to gene dosage. Clinical characteristics of patients with duplications were rather typical for PD [192,194], while patients with triplications had lower age at onset,rapid progression, and more often dementia [196]. Most commonly, the duplications and triplications occurred de novo [196].…”

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Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…PD pathogenesis involves genetic abnormalities, protein misfolding, defective mitophagy and neuroinflammation. Loci multiplication and mutations in the -synuclein gene, SNCA, predispose to autosomal dominant PD [97][98][99]. However, most patients have sporadic forms of PD in which aging and inefficient proteasome degradation results in accumulation of -synuclein and inflammation [100][101][102][103][104].…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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“…Rare CNVs are important genetic causes of human diseases, especially neurological disorders including PD [26][27][28][29][30][31][32] .…”

Section: No Copy Number Variations Of the Cp Gene In Pd Patientsmentioning

confidence: 99%

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

et al. 2015

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Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson's disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/ iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were signifi cantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no signifi cant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

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α-synuclein locus duplication as a cause of familial Parkinson's disease

Cited by 1,847 publications

References 5 publications

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

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