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.
Subject(s)
Parkinson Disease/genetics , Genes, Dominant , Genes, Recessive , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Mutation , Parkinsonian Disorders/genetics , Protein Kinases/genetics , Protein Serine-Threonine Kinases/genetics , Proton-Translocating ATPases/genetics , Ubiquitin-Protein Ligases/genetics , alpha-Synuclein/geneticsABSTRACT
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.
Subject(s)
DNA-Binding Proteins/metabolism , Neurons/physiology , Parkinson Disease/physiopathology , Transcription Factors/metabolism , Transcriptional Activation/physiology , alpha-Synuclein/genetics , Cell Line, Tumor , DNA-Binding Proteins/genetics , Gene Expression Regulation/physiology , Humans , Neuroblastoma , Neurons/cytology , Nuclear Receptor Subfamily 4, Group A, Member 2 , Parkinson Disease/genetics , Promoter Regions, Genetic/physiology , RNA, Small Interfering , Transcription Factors/genetics , TransfectionABSTRACT
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.
Subject(s)
Mutation/physiology , Parkinson Disease/genetics , Protein Kinases/genetics , Adult , Age of Onset , Aged , Alleles , Cells, Cultured , Chromosomes/genetics , Computational Biology , DNA Mutational Analysis , Female , Flow Cytometry , Gene Frequency , Heterozygote , Humans , Male , Membrane Potentials/physiology , Middle Aged , Mitochondria/physiology , Open Reading Frames/genetics , TransfectionABSTRACT
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Gene mutations have been found in rare familial forms of PD, with mutations in parkin being the most common cause. Oxidative stresses have also been implicated as an important contributing factor in the pathogenesis of PD. Currently, there is accumulating evidence that parkin may play a role in maintaining mitochondrial function and preventing oxidative stress. We demonstrated here that parkin is up-regulated when SH-SY5Y dopaminergic neuroblastoma cells are exposed to the oxidant dopamine. The up-regulation of parkin appeared to be due to transcriptional activation as luciferase assays confirmed that specific parkin promoter constructs could confer enhanced transcriptional activation in response to dopamine. Moreover, this effect was also seen when SH-SY5Y cells were subjected to another oxidative stress, 1-methyl-4-phenylpyridinium. In parallel with these studies, we also observed similar transcriptional activation of the parkin coregulated gene by oxidative stress. This is the first demonstration that parkin expression is up-regulated by oxidative stresses and may suggest that this might be a general neuroprotective response of parkin to oxidative stresses.
