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Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

ABSTRACT: Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1-42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N?=?1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ?4, was associated with CSF amyloid beta1-42 levels (effect?=?-?0.5, p?=?9.2?×?10-19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p?=?0.035) and the genomic architecture of CSF amyloid beta1-42 (R2?=?2.29%; p?=?2.5?×?10-11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1-42 levels (p?=?7.3?×?10-04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1-42 plays a role in Parkinson's disease (p?=?1.4?×?10-05) and age at onset (p?=?7.6?×?10-06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ?4 allele was associated with significantly lower levels of CSF amyloid beta1-42 (p?=?3.8?×?10-06), higher mean cortical binding potentials (p?=?5.8?×?10-08), and higher Braak amyloid beta score (p?=?4.4?×?10-04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta1-42, and APOE.

SUBMITTER: Ibanez L

PROVIDER: S-EPMC7678051 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

Ibanez Laura L Bahena Jorge A JA Yang Chengran C Dube Umber U Farias Fabiana H G FHG Budde John P JP Bergmann Kristy K Brenner-Webster Carol C Morris John C JC Perrin Richard J RJ Cairns Nigel J NJ O'Donnell John J Álvarez Ignacio I Diez-Fairen Monica M Aguilar Miquel M Miller Rebecca R Davis Albert A AA Pastor Pau P Kotzbauer Paul P Campbell Meghan C MC Perlmutter Joel S JS Rhinn Herve H Harari Oscar O Cruchaga Carlos C Benitez Bruno A BA

Acta neuropathologica communications 20201119 1

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta<sub>1-42</sub>, total tau, and phosphorylated tau<sub>181</sub> as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson' ...[more]

PMID: 33213513

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Project description:Tau gene has been consistently associated with the risk of Parkinson disease in recent genome wide association studies. In addition, alterations of the levels of total tau, phosphorylated tau [181P], and amyloid beta 1-42 in cerebrospinal fluid have been reported in patients with sporadic Parkinson disease and asymptomatic carriers of leucine-rich repeat kinase 2 mutations, in patterns that clearly differ from those typically described for patients with Alzheimer disease. To further determine the potential roles of these molecules in Parkinson disease pathogenesis and/or in tracking the disease progression, especially at early stages, the current study assessed all three proteins in 403 Parkinson disease patients enrolled in the DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) placebo-controlled clinical trial, the largest cohort to date with cerebrospinal fluid samples collected longitudinally. These initially drug-naive patients at early disease stages were clinically evaluated, and cerebrospinal fluid was collected at baseline and then at endpoint, defined as the time at which symptomatic anti-Parkinson disease medications were determined to be required. General linear models were used to test for associations between baseline cerebrospinal fluid biomarker levels or their rates of change and changes in the Unified Parkinson Disease Rating Scale (total or part III motor score) over time. Robust associations among candidate markers are readily noted. Baseline levels of amyloid beta were weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores. Baseline phosphorylated tau/total tau and phosphorylated tau/amyloid beta were significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change. While medications (deprenyl and/or tocopherol) did not appear to alter biomarkers appreciably, a weak but significant positive correlation between the rate of change in total tau or total tau/amyloid beta levels and the change of the Unified Parkinson Disease Rating Scale was observed. Notably, these correlations did not appear to be influenced by APOE genotype. These results are one of the very first pieces of evidence suggesting that tau and amyloid beta are critically involved in early Parkinson disease progression, potentially by a different mechanism than that in Alzheimer disease, although their applications as Parkinson disease progression markers will likely require the addition of other proteins.

Project description:Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid ?42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid ?42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

Dataset Information

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

Publications

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

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