Genome‐wide data mining to construct a competing endogenous RNA network and reveal the pivotal therapeutic targets of Parkinson's disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01072-8 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Laura Ibanez ◽

Jorge A. Bahena ◽

Chengran Yang ◽

Umber Dube ◽

Fabiana H. G. Farias ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Amyloid Beta ◽

Alpha Synuclein ◽

Phosphorylated Tau ◽

Polygenic Risk ◽

Total Tau ◽

Genomic Architecture ◽

Genome Wide ◽

Csf Biomarker

AbstractAlpha-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 ε4, 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 ε4 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.

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A review of genome-wide transcriptomics studies in Parkinson's disease

European Journal of Neuroscience ◽

10.1111/ejn.13760 ◽

2017 ◽

Vol 47 (1) ◽

pp. 1-16 ◽

Cited By ~ 38

Author(s):

Genevie Borrageiro ◽

William Haylett ◽

Soraya Seedat ◽

Helena Kuivaniemi ◽

Soraya Bardien

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genome Wide

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Improving Diversity in Parkinson's Disease Genetics: Findings from the First‐Ever Genome‐Wide Association Study in Latinos

Movement Disorders ◽

10.1002/mds.28782 ◽

2021 ◽

Author(s):

Inas Elsayed ◽

Isabelle Francesca Foote

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson’s Disease

Molecular Neurodegeneration ◽

10.1186/s13024-016-0097-0 ◽

2016 ◽

Vol 11 (1) ◽

Cited By ~ 38

Author(s):

Bruno A. Benitez ◽

Albert A. Davis ◽

Sheng Chih Jin ◽

Laura Ibanez ◽

Sara Ortega-Cubero ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Linking a genome-wide association study signal to aLRRK2coding variant in Parkinson's disease

Movement Disorders ◽

10.1002/mds.26495 ◽

2015 ◽

Vol 31 (4) ◽

pp. 484-487 ◽

Cited By ~ 4

Author(s):

Jia Nee Foo ◽

Sun Ju Chung ◽

Louis C. Tan ◽

Herty Liany ◽

Ho-Sung Ryu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

10.1101/2021.09.17.21263343 ◽

2021 ◽

Author(s):

Aoji Xie ◽

Elizabeth Ensink ◽

Peipei Li ◽

Juozas Gordevicius ◽

Lee L. Marshall ◽

...

Keyword(s):

Parkinson’S Disease ◽

Dna Methylation ◽

Parkinson's Disease ◽

Depressive Symptoms ◽

Gut Microbiome ◽

Whole Blood ◽

Blood Samples ◽

Targeted Bisulfite Sequencing ◽

Genome Wide ◽

Whole Blood Samples

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

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DEFINING CANDIDATE PARKINSON’S DISEASE GENES THROUGH THE ANALYSIS OF GENOME-WIDE HOMOZYGOSITY

10.1101/2020.11.23.20235671 ◽

2020 ◽

Author(s):

Steven J Lubbe ◽

Yvette C. Wong ◽

Bernabe Bustos ◽

Soojin Kim ◽

Jana Vandrovcova ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Disease Genes ◽

Compound Heterozygous ◽

Genome Wide ◽

Biallelic Mutations ◽

Functional Analyses

ABSTRACTEarly-onset Parkinson’s disease (EOPD) can be caused by biallelic mutations in PRKN, DJ1 and PINK1. However, while the identification of novel genes is becoming increasingly challenging, new insights into EOPD genetics have important relevance for understanding the pathways driving disease pathogenesis. Here, using extended runs of homozygosity (ROH) >8Mb as a marker for possible autosomal recessive inheritance, we identified 90 EOPD patients with extended ROH. Investigating rare, damaging homozygous variants to identify candidate genes for EOPD, 81 genes were prioritised. Through the assessment of biallelic (homozygous and compound heterozygous) variant frequencies in cases and controls from three independent cohorts totalling 3,381 PD patients and 2,463 controls, we identified two biallelic MIEF1 variant carriers among EOPD patients. We further investigated the role of disease-associated variants in MIEF1 which encodes for MID51, an outer mitochondrial membrane protein, and found that putative EOPD-associated variants in MID51 preferentially disrupted its oligomerization state. These findings provide further support for the role of mitochondrial dysfunction in the development of PD. Together, we have used genome-wide homozygosity mapping to identify potential EOPD genes, and future studies incorporating expanded datasets and further functional analyses will help to determine their roles in disease aetiology.

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