Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are most frequent known genetic risk factor for Parkinson's disease. Reduced glucocerebrosidase and α-synuclein accumulation directly related cell models of We investigated relationships between disease-specific deficits, glucocerebrosidase-related pathways, levels brain tissue from subjects with sporadic disease without GBA1 mutations. Brain regions a disease-related increase were assessed autopsy samples (n =...

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect phenotype. Here, we amplified aggregates from PD MSA brain extracts analyzed the conformational properties using fluorescent probes, NMR spectroscopy electron paramagnetic resonance. We also generated several vitro polymorphs. found...

Abstract Many genetic risk factors for Parkinson’s disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against disease. Moreover, the hallmark pathological protein, α-synuclein, has lipid membrane function pathways dysregulated in endosome–lysosome system synaptic signalling rely heavily on dynamics. Despite potential role lipids disease, most research to date been protein-centric, with large-scale, untargeted serum CSF lipidomic comparisons...

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected macrophages, microglia, neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins can also regulate phagocytosis modulate processing amyloid precursor protein (APP) generate Alzheimer's disease (AD) amyloid-β (Aβ) peptide. Genome-wide association studies have indicated that single nucleotide polymorphisms confer increased risk for late-onset AD; however, role plays AD context unknown. In...

Maintenance of an adequate supply cholesterol is important for neuronal function, whereas excess promotes amyloid precursor protein (APP) cleavage generating toxic amyloid-β (Aβ) peptides. To gain insights into the pathways that regulate level, we investigated potential reconstituted apolipoprotein E (apoE) discs, resembling nascent lipoprotein complexes in central nervous system, to stimulate [3H]cholesterol efflux. ApoE discs potently accelerated efflux from primary human neurons and cell...

We present a lipidomics analysis of human Parkinson's disease tissues. have focused on the primary visual cortex, region that is devoid pathological changes and Lewy bodies; two additional regions, amygdala anterior cingulate cortex which contain bodies at different stages but do not as severe degeneration substantia nigra.Using liquid chromatography mass spectrometry techniques for an initial screen 200 lipid species, significant in 79 sphingolipid, glycerophospholipid cholesterol species...

See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article. In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in microtubule-associated protein tau (MAPT) gene chromosome 17 families and parkinsonism (FTDP-17). However, it was soon discovered that 50% these had nearby mutation...

Abstract Missense mutations in glucocerebrosidase ( GBA1 ) that impair the activity of encoded lysosomal lipid metabolism enzyme (GCase) are linked to an increased risk Parkinson’s disease. However, reduced GCase is also found brain tissue from disease patients without mutations, implicating dysfunction more common idiopathic form very highly expressed monocytes, and thus we measured blood samples recently diagnosed patients. Flow cytometry immunoblotting assays were used measure levels...

Five ATP-binding cassette (ABC) subfamily-A transporters (ABCA1, ABCA2, ABCA3, ABCA7 and ABCA8) are expressed in the brain. These may regulate brain lipid transport; however, their relative expression level isolated human cells is unknown. We developed real-time polymerase chain reaction assays to quantify of these genes neurons, astrocytes, oligodendrocytes, microglia cell lines. Neurons predominantly ABCA1 ABCA3; astrocytes ABCA1, ABCA2 oligodendrocytes ABCA3. Although ABCA8 was relatively...

Mutations in the A class of ATP-binding cassette transporters (ABCA) are causally implicated three human diseases: Tangier disease (ABCA1), Stargadt's macular degeneration (ABCA4), and neonatal respiratory failure (ABCA3). Both ABCA1 ABCA4 have been shown to transport lipids across cellular membranes, ABCA3 may play a similar role transporting pulmonary surfactant. Although functions other 10 ABCA identified genome remain obscure, ABCA7-transfected cells efflux response stimulation by...

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and, like its closest homolog ABCA1, belongs to ABCA subfamily of full-length ABC transporters. ABCA1 promotes cellular cholesterol efflux lipid-free apolipoprotein acceptors and also inhibits production neurotoxic beta-amyloid (Abeta) peptides vitro. The potential functions ABCA7 are unknown. This study investigated ability regulate extracellular modulate Abeta production. transient expression human embryonic kidney cells...

ABSTRACT Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence risk and may act via an epigenetic mechanism. The microtubule‐associated protein tau ( MAPT ) susceptibility gene idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite‐treated DNA in leukocyte cohort (358 PD patients 1084 controls) two brain cohorts (Brain1, comprising 69 cerebellum controls; Brain2, 3 regions from 28 12 controls). In vitro assays involved...

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 strongly associated with AD. In vitro evidence suggests role related to phagocytic activity. Deletion mouse model AD exacerbates cerebral plaque load. However, biological brain pathogenesis unknown. We show highly expressed microglia when monocytes are differentiated into macrophages....

Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA the presence α-synuclein deposits in oligodendrocytes, myelin-producing support cells brain. Brain pathology vitro studies indicate that myelin instability may be an early event pathogenesis MSA. Lipid major constituent (78% w/w) has been implicated dysfunction However, changes, if any, lipid level/distribution...

Studies investigating the pathogenic role of microtubule associated protein tau (MAPT) gene in Parkinson's disease (PD) have indicated that DNA methylation promoter region is aberrant disease, leading to dysregulated MAPT expression. We examined two potential regulators expression respect PD, a promoter-associated long non-coding RNA MAPT-AS1, and methyltransferases (DNMTs), enzymes responsible for new maintenance methylation. assessed relationship between levels candidate DNMT1, DNMT3A...

Abstract Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that considered to be on the same disease spectrum because of overlapping genetic, pathological clinical traits. Changes in serum proteins FTD ALS poorly understood, currently no definitive biomarkers exist for diagnosing or monitoring progression either disease. Here we applied quantitative discovery proteomics analyze protein changes (N = 72) 28) patient compared controls 22)....

Abstract Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of number human diseases with improved diagnosis development biomarkers. Understanding lipid changes neurodegenerative particularly important because fact that make up >50% brain tissues. Frontotemporal dementia (FTD) common cause early onset dementia, characterized by atrophy frontal temporal regions, concomitant loss dyslipidemia. However, little known about link between dyslipidemia...

Parkinson's disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three stages PD have been proposed (a silent period when begins, prodromal with subtle focal manifestations, and clinical PD) evidence that cortex abnormalities occur to produce PD[8]. We directly assess structural in primary corticospinal tract using parallel analyses longitudinal cross-sectional...

Abstract Lipid peroxidation is a process of oxidative degradation cellular lipids that increasingly recognized as an important factor in the pathogenesis neurodegenerative diseases. We were therefore interested manifestation lipid synucleinopathies, group diseases characterized by central pathology α-synuclein aggregates, including Parkinson’s disease, multiple system atrophy, dementia with Lewy bodies and Alzheimer’s disease bodies. assessed products, aldehydes, amygdala, common...

Abstract Objective biomarkers for Parkinson’s Disease (PD) could aid early and specific diagnosis, effective monitoring of disease progression, improved design interpretation clinical trials. Although alpha-synuclein remains a biomarker candidate interest, the multifactorial heterogenous nature PD highlights need panel. Ideal candidates include markers that are detectable in easily accessible samples, (ideally blood) reflect underlying pathological process PD. In present study, we explored...

Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by fact they comprise approximately 8% genome. been implicated in pathogenesis neurodegenerative diseases, a group CNS diseases characterized progressive loss structure and function neurons, resulting cell death multiple physiological dysfunctions. Much evidence indicates initiators or drivers...

Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates lysosomal dysfunction pivotal in pathogenesis of PD, typically characterized by dysregulation sphingolipids lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) transporter mediates removal excess sphingomyelin from We therefore investigated whether expression levels ABCA5 are associated with and α-synuclein pathology PD. Firstly, we undertook...