Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.
Dis Model Mech
; 10(5): 619-631, 2017 05 01.
Article
en En
| MEDLINE
| ID: mdl-28108469
ABSTRACT
Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
ARN
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Biomarcadores
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Predisposición Genética a la Enfermedad
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Enfermedad por Cuerpos de Lewy
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Trastorno de la Conducta del Sueño REM
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Proteínas Adaptadoras del Transporte Vesicular
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Alfa-Sinucleína
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Proteínas del Tejido Nervioso
Tipo de estudio:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Female
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Humans
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Middle aged
Idioma:
En
Revista:
Dis Model Mech
Asunto de la revista:
MEDICINA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Alemania