Identifying robust and reliable volatile organic compounds in human sebum for biomarker discovery.

Sebum from sebaceous glands is a rich source of volatile organic compounds (VOCs) that can readily be sampled non-invasively from the surface of skin. The VOC profiles of sebum can then be used to obtain information regarding different medical conditions including diabetes and Parkinson's Disease. However, the effects of sampling approaches and environmental factors on sebum VOC profiles are not established and the confident attribution of VOCs to disease states needs to be free of extraneous influences such as sampling materials and preparatory conditions.

Redefining the hypotheses driving Parkinson's diseases research.

Parkinson's disease (PD) research has largely focused on the disease as a single entity centred on the development of neuronal pathology within the central nervous system. However, there is growing recognition that PD is not a single entity but instead reflects multiple diseases, in which different combinations of environmental, genetic and potential comorbid factors interact to direct individual disease trajectories. Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD.

Establishing gene regulatory networks from Parkinson's disease risk loci.

The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson's disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with Parkinson's disease risk variants, we utilized an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci) data. We identified 518 genes subject to regulation by 76 Parkinson's variants across 49 tissues, whicih encompass 36 peripheral and 13 CNS tissues.

Machine Learning Identifies Six Genetic Variants and Alterations in the Heart Atrial Appendage as Key Contributors to PD Risk Predictivity.

Parkinson's disease (PD) is a complex neurodegenerative disease with a range of causes and clinical presentations. Over 76 genetic loci (comprising 90 SNPs) have been associated with PD by the most recent GWAS meta-analysis. Most of these PD-associated variants are located in non-coding regions of the genome and it is difficult to understand what they are doing and how they contribute to the aetiology of PD.

Defining early changes in Alzheimer's disease from RNA sequencing of brain regions differentially affected by pathology.

Tau pathology in Alzheimer's disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression.

De Novo Gene Variants and Familial Bipolar Disorder.

This case-control study explores de novo candidate gene variants in 18 multiplex families with bipolar disorder.

Regulation of mitochondrial metabolism in murine skeletal muscle by the medium-chain fatty acid receptor Gpr84.

Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium-chain fatty acid (MCFA) receptor G-protein-coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue.

Publisher Correction: Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease.

In the version of this article initially published, the legends for Supplementary Figs. 4-8 and 10-14 contained errors. The Supplementary Figure legends have been corrected in the HTML and PDF versions of the article.

Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease.

Enhancers function as DNA logic gates and may control specialized functions of billions of neurons. Here we show a tailored program of noncoding genome elements active in situ in physiologically distinct dopamine neurons of the human brain. We found 71,022 transcribed noncoding elements, many of which were consistent with active enhancers and with regulatory mechanisms in zebrafish and mouse brains.

The central role of noncoding RNA in the brain.

Less than 3% of the human genome generates protein-coding transcripts; the majority, far from being strewn with evolutionary "junk," is dynamically transcribed into non(protein)-coding RNAs (ncRNAs). These ncRNAs provide another provide another, previously hidden, level of regulatory information that appears to be involved in hard- and soft-wired epigentic processes. The extensive and intricate level of gene regulation provided by ncRNAs may be the major driver for the accelerated development of the human brain and its associated increase in complexity and cognition.

Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes.

α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2(-/-) patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression in primary neurons confers zinc resistance.

ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies.

Background: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson's disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.

αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson's Disease?

Parkinson's Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown.

The role of the Parkinson's disease gene PARK9 in essential cellular pathways and the manganese homeostasis network in yeast.

YPK9 (Yeast PARK9; also known as YOR291W) is a non-essential yeast gene predicted by sequence to encode a transmembrane P-type transport ATPase. However, its substrate specificity is unknown. Mutations in the human homolog of YPK9, ATP13A2/PARK9, have been linked to genetic forms of early onset parkinsonism.

Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism.

Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models.

alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression.

Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype.

Introduction: Mutations in the pore domain of the human ether-a-go-go-related gene (hERG) potassium channel are associated with higher risk of sudden death. However, in many kindreds clinical presentation is variable, making it hard to predict risk. We hypothesized that in vitro phenotyping of the intrinsic severity of individual mutations can assist with risk stratification.

Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity.

Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited.

ERADicate ER stress or die trying.

Stress within the endoplasmic reticulum (ER) induces a sophisticated network of pathways termed the unfolded protein response (UPR), which is mediated through the ER transmembrane sensors PERK, ATF6, and IRE1. The UPR coordinates the temporary downregulation of protein translation, the upregulation of ER chaperones and folding machinery, and the enhanced expression of components necessary for ER-associated degradation (ERAD) essential for decreasing ER stress by clearing terminally misfolded proteins from the ER. Repetitive but futile folding attempts not only prolong ER stress but can also result in reactive oxygen species (ROS) generation, both of which may result in cell death.

Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals.

Most misfolded secretory proteins remain in the endoplasmic reticulum (ER) and are degraded by ER-associated degradation (ERAD). However, some misfolded proteins exit the ER and traffic to the Golgi before degradation. Using model misfolded substrates, with or without defined ER exit signals, we found misfolded proteins can depart the ER by continuing to exhibit the functional export signals present in the corresponding correctly folded proteins.