Parkinson Disease: Yang YX

Yang YX, Wood NW, Latchman DS. · Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK. · Neuroreport. · Pubmed #19151598 No free full text.

Abstract: Parkinson's disease is the second most common neurodegenerative disorder and remains incurable. Considerable progress has been made in understanding the molecular mechanisms of this disease, in particular, a distinct set of genes have emerged, whose dysfunctional regulation is strongly associated with the condition. These genes include alpha-synuclein, parkin, PTEN induced Putative Kinase 1 (PINK1), DJ-1, Leucine Rich Repeat Kinase 2 (LRRK2) and ATP13A2. Here we discuss what has been learnt in the study of these genes and how these genes may contribute to the pathogenesis of Parkinson's disease through different molecular pathways, and consider how these pathways might converge to lead to the onset of Parkinson's disease.

Sleiman PM, Healy DG, Muqit MM, Yang YX, Van Der Brug M, Holton JL, Revesz T, Quinn NP, Bhatia K, Diss JK, Lees AJ, Cookson MR, Latchman DS, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK. · Neurosci Lett. · Pubmed #19429166 No free full text.

Abstract: OBJECTIVE: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C>T). RESULTS: We have performed expression studies in neuronal cell lines showing that the c.-309C>T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C>T mutation and show a 3.48+/-1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C>T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. CONCLUSIONS: Our findings indicate the c.-309C>T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation.

Yang YX, Latchman DS. · Medical Molecular Biology Unit, Institute of Child Health, University College London, UK. · Neuroreport. · Pubmed #18463503 No free full text.

Abstract: Parkinson's disease is one of the most common neurodegenerative disorders and still remains incurable. The condition is linked to mutations and alterations in expression in several genes, in particular that encoding alpha-synuclein. Mutations in Nurr1 leading to a reduction in expression were also found to lead to Parkinson's disease. In view of the importance of gene regulation in Parkinson's disease, we examined the effect of changes in Nurr1 expression on alpha-synuclein expression. Nurr1 was shown to be involved in the regulation of alpha-synuclein, as decreased expression of Nurr1, which has been found in Parkinson's disease patients with Nurr1 mutations, was shown to transcriptionally increase alpha-synuclein expression.

Abou-Sleiman PM, Muqit MM, McDonald NQ, Yang YX, Gandhi S, Healy DG, Harvey K, Harvey RJ, Deas E, Bhatia K, Quinn N, Lees A, Latchman DS, Wood NW. · Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom. · Ann Neurol. · Pubmed #16969854 No free full text.

Abstract: OBJECTIVE: To investigate the significance of PINK1 mutations in sporadic Parkinson's disease (PD). METHODS: We determined the frequency of PINK1 mutations by direct sequencing in a large series of PD patients with apparently sporadic disease (n = 768). RESULTS: Twelve heterozygous mutations were identified, nine in PD patients and three in control subjects. INTERPRETATION: Given the difficulty in interpreting the pathogenic significance of the heterozygous mutations that have already been reported in parkin and DJ-1, we first determined the frequency of heterozygous PINK1 mutations in the general population by sequencing a large number of control subjects (n = 768), then subsequently assessed their functional significance by examining their effects on stress-induced alterations to the mitochondrial membrane potential (DeltaPsim). We demonstrate an enrichment of heterozygous mutations in sporadic PD patients compared with matched control subjects (1.2% in PD vs 0.4% in control subjects). Furthermore, we show that they adversely affect DeltaPsim in a similar way to the familial G309D mutation. Although it remains difficult to conclusively demonstrate the pathogenicity of heterozygous mutations, the results of this study and the previously reported subclinical nigrostriatal dysfunction in carriers of heterozygous PINK1 mutations suggest the possibility that these heterozygous mutations are a significant risk factor in the development of later onset PD.