Independent and joint effects of the <i>MAPT</i> and <i>SNCA</i> genes in Parkinson disease

Elbaz, Alexis; Ross, Owen A.; Ioannidis, John P. A.; Soto‐Ortolaza, Alexandra I.; Moisan, Frédéric; Aasly, Jan; Annesi, Grazia; Bozi, Maria; Brighina, Laura; Chartier-Harlin, Marie-Christine; Destée, Alain; Ferrarese, Carlo; Ferraris, Alessandro; Gibson, J. M.; Gispert, Suzana; Hadjigeorgiou, Georgios M.; Jasińska-Myga, Barbara; Klein, Christine; Krüger, Rejko; Lambert, Jean‐Charles; Lohmann, Katja; Loo, Simone van de; Loriot, Marie‐Anne; Lynch, Timothy; Mellick, George D.; Mutez, Eugénie; Nilsson, Christer; Opala, Grzegorz; Puschmann, Andreas; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Stefanis, Leonidas; Uitti, Ryan J.; Valente, Enza Maria; Vilariño‐Güell, Carles; Wirdefeldt, Karin; Wszołek, Zbigniew K.; Xiromerisiou, Georgia; Maraganore, Demetrius M.; Farrer, Matthew J.

doi:10.1002/ana.22321

Cited by 86 publications

(80 citation statements)

References 49 publications

(126 reference statements)

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“…However, in neurons LRRK2 plays a role in trans-Golgi protein sorting (25), morphogenesis (22) and synaptic endocytosis (26). Genetic variability in SNCA and MAPT are most commonly associated with familial and sporadic PD (27). In neurons, SNCA predominantly localizes to presynaptic terminals and is involved in the generation and maintenance of vesicle pools, chaperoning SNARE complex assembly and in synaptic vesicle recycling upon neuronal stimulation (28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

DNAJC13 mutations in Parkinson disease

Vilariño‐Güell

Rajput

Milnerwood

et al. 2013

Human Molecular Genetics

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A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case–control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch–German–Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

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Section: Discussionmentioning

confidence: 99%

DNAJC13 mutations in Parkinson disease

Vilariño‐Güell

Rajput

Milnerwood

et al. 2013

Human Molecular Genetics

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261

229

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“…One potential mechanism leading to neuronal death is invasion of α-tubulin oligomers which affects the dynamics of microtubules (modified after [398] [569]. Independent and joint effects of the SNCA and MAPT (tau) genes in PD have been described [570,571], and the MAPT H1 haplotype has been reported to be a risk factor for PD [572], while it reduces the severity of AD pathology [573]. Polymorphisms between SNCA and MAPT interact to influence the rate of progression of PD, which is more prominent in the early stages of the disease [574].…”

Section: α-Synuclein and Protein Interactionsmentioning

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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“…A previous study demonstrated that the association pattern between rs11931074 and PD was consistent with a dominant model of association and nearly consistent with an additive model of association [12]. We investigated the relationship between rs11931074 and a-synuclein levels in both models in a combined group consisting of PD patients and control subjects.…”

Section: Resultsmentioning

confidence: 90%

Variant in the 3′ region of SNCA associated with Parkinson’s disease and serum α-synuclein levels

Tang

Guo

et al. 2011

J Neurol

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Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of Lewy bodies is a major pathological change of PD. α-synuclein is the main component of Lewy bodies and is encoded by the SNCA gene. Mutations in the SNCA gene mainly result in rare familial forms of PD, while genetic variability in the SNCA gene modulates susceptibility to sporadic PD. Recent studies have suggested that levels of α-synuclein in extracellular biological fluid are associated with PD and implicated α-synuclein as a potential biomarker for PD diagnosis and severity. We studied serum α-synuclein concentration and two polymorphic variants of SNCA (Rep1 and rs11931074) in 110 sporadic PD patients and 136 controls. We further explored the influence of the two polymorphisms on the expression levels of serum α-synuclein. Soluble α-synuclein was detected in serum in all subjects, with no statistically significant difference between PD patients and controls (p = 0.611). Different Rep1 alleles and genotypes did not influence the expression of serum α-synuclein. The frequency of allele T of rs11931074 was significantly elevated in PD patients (p = 0.041), and was correlated with decreased serum α-synuclein in both dominant (p = 0.011) and additive (p = 0.008) models of association.

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Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Cited by 86 publications

References 49 publications

DNAJC13 mutations in Parkinson disease

DNAJC13 mutations in Parkinson disease

The role of α-synuclein in neurodegeneration — An update

Variant in the 3′ region of SNCA associated with Parkinson’s disease and serum α-synuclein levels

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