Functional Interaction Between α-Synuclein and Nurr1 in Dopaminergic Neurons.

Increased expression of alpha-synuclein (ASYN) and decreased expression of Nurr1 are associated with Parkinson's disease (PD) pathogenesis. These two proteins interact functionally and ASYN overexpression suppresses Nurr1 levels. ASYN pan-neuronal overexpression coupled with Nurr1 hemizygosity followed by Nurr1 repression in aging mice results in the manifestation of a typical PD-related phenotype and pathology.

Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: Data analysis of the Hellenic Biobank of Parkinson's disease.

Background: Age at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting.

Objective: The aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD).

Methods: HBPD contains information of PD cases from two centers in Greece during 2006-2017.

α-Synuclein Induces the GSK-3-Mediated Phosphorylation and Degradation of NURR1 and Loss of Dopaminergic Hallmarks.

In Parkinson's disease, the dysfunction of the dopaminergic nigrostriatal tract involves the loss of function of dopaminergic neurons of the substantia nigra pars compacta followed by death of these neurons. The functional recovery of these neurons requires a deep knowledge of the molecules that maintain the dopaminergic phenotype during adulthood and the mechanisms that subvert their activity. Previous studies have shown that transcription factor NURR1, involved in differentiation and maintenance of the dopaminergic phenotype, is downregulated by α-synuclein (α-SYN).

Nurr1 repression mediates cardinal features of Parkinson's disease in α-synuclein transgenic mice.

Duplication/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson's disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice.

The relationship between environmental factors and different Parkinson's disease subtypes in Greece: Data analysis of the Hellenic Biobank of Parkinson's disease.

Introduction: The aim of this study is to investigate the association between environmental factors (smoking, coffee, pesticide exposure) and Parkinson's disease (PD) subtypes (early-onset, mid-and-late onset, familial and sporadic) in the Greek population.

Methods: The Hellenic Biobank of PD recorded information of PD cases and controls from two centers in Greece during 2006-2017. Patients with the A53T mutation in SNCA or GBA mutations were excluded.

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement.

Structure-based virtual screening for drug discovery: principles, applications and recent advances.

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits.

Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Background: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.

Methods: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

Background: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.

Selective noradrenergic vulnerability in α-synuclein transgenic mice.

Classical pathological signs of Parkinson's disease (PD) include loss of dopaminergic neurons in substantia nigra (SN) and noradrenergic neurons in locus coeruleus (LC), and deposition of Lewy bodies rich in the presynaptic protein alpha-synuclein (ASYN). Mammalian genetic models based on ASYN overexpression, however, have generally not reproduced the profound dopaminergic deficit of PD and do not display classical PD phenotypes. In the current study we examined these catecholaminergic systems in transgenic (Tg) mice expressing the A53T mutant of human ASYN under the Prion promoter.

The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone.

The Kiss1 gene codes for kisspeptin, which binds to GPR54, a G-protein-coupled receptor. Kisspeptin and GPR54 are expressed in discrete regions of the forebrain, and they have been implicated in the neuroendocrine regulation of reproduction. Kiss1-expressing neurons are thought to regulate the secretion of gonadotropin-releasing hormone (GnRH) and thus coordinate the estrous cycle in rodents; however, the precise role of kisspeptin-GPR54 signaling in the regulation of gonadotropin secretion is unknown.

Large-scale, saturating insertional mutagenesis of the mouse genome.

We describe the construction of a large-scale, orderly assembly of mutant ES cells, generated with retroviral insertions and having mutational coverage in >90% of mouse genes. We also describe a method for isolating ES cell clones with mutations in specific genes of interest from this library. This approach, which combines saturating random mutagenesis with targeted selection of mutations in the genes of interest, was successfully applied to the gene families of G protein-coupled receptors (GPCRs) and nuclear receptors.

Functional analysis of MRG-1: the ortholog of human MRG15 in Caenorhabditis elegans.

Mortality Factor on Chromosome 4 (MORF4) induces senescence in several immortal human cell lines. MORF-related gene on chromosome 15 (MRG15), another expressed family member, is highly conserved and expressed in yeast to humans. To determine the biological functions of human MRG15 (hMRG15) we used RNA-mediated interference (RNAi) to silence mrg-1, the Caenorhabditis elegans ortholog, and its closest homolog Y37D8A.

The G protein-coupled receptor repertoires of human and mouse.

Diverse members of the G protein-coupled receptor (GPCR) superfamily participate in a variety of physiological functions and are major targets of pharmaceutical drugs. Here we report that the repertoire of GPCRs for endogenous ligands consists of 367 receptors in humans and 392 in mice. Included here are 26 human and 83 mouse GPCRs not previously identified.

Mutations in NR4A2 associated with familial Parkinson disease.

NR4A2, encoding a member of nuclear receptor superfamily, is essential for the differentiation of the nigral dopaminergic neurons. To determine whether NR4A2 is a susceptibility gene for Parkinson disease, we carried out genetic analyses in 201 individuals affected with Parkinson disease and 221 age-matched unaffected controls. We identified two mutations in NR4A2 associated with Parkinson disease (-291Tdel and -245T-->G), which map to the first exon of NR4A2 and affect one allele in 10 of 107 individuals with familial Parkinson disease but not in any individuals with sporadic Parkinson disease (n = 94) or in unaffected controls (n = 221).