Showing papers on "PARK7 published in 2005"

Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress

Abstract: Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.

The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis

Abstract: Mutations in the DJ-1 gene cause early-onset autosomal recessive Parkinson's disease (PD), although the role of DJ-1 in the degeneration of dopaminergic neurons is unresolved Here we show that the major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multifunctional regulators of transcription and RNA metabolism PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF Unlike pathogenic DJ-1 mutants, wild-type DJ-1 acts to inhibit the transcriptional silencing activity of the PSF In addition, the transcriptional silencer PSF induces neuronal apoptosis, which can be reversed by wild-type DJ-1 but to a lesser extent by PD-associated DJ-1 mutants DJ-1-specific small interfering RNA sensitizes cells to PSF-induced apoptosis Both DJ-1 and p54nrb block oxidative stress and mutant alpha-synuclein-induced cell death Thus, DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic neurons vulnerable to apoptosis and may contribute to the pathogenesis of PD

LRRK2: both a cause and a risk factor for Parkinson disease?

Abstract: It is now clear that genetic risk is important in the pathogenesis of Parkinson disease (PD) Initial studies focusing on families with clear mendelian inheritance led to the identification of five genes with a confirmed role in PD etiology: α-synuclein ( SCNA ; PARK1), parkin ( PRKN ; PARK2), PTEN-induced putative kinase 1 ( PINK1 ; PARK6), oncogene DJ-1 ( DJ-1 ; PARK7), and leucine-rich repeat kinase 2 ( LRRK2 ; PARK8) Mutations in three of these genes, SCNA , PINK1 , and DJ-1 , are rare causes of PD1 However, the role of parkin in PD etiology has been greatly expanded Mutations in parkin were thought initially to cause only early-onset, autosomal recessive PD2 Further studies have shown that mutations in parkin can be found among individuals with adult-onset disease3 and suggest that heterozygous mutations in parkin might act as a susceptibility factor, increasing the risk of PD4 LRRK2 seems likely to contribute to more typical, idiopathic PD Mutations have been reported in patients of all ages However, LRRK2 has posed major challenges for researchers The most formidable is the size of the gene LRRK2 includes 51 exons As a result, thorough screening of this gene to identify novel mutations is costly and time-consuming Three articles in this issue of Neurology have taken different approaches to this difficult problem Two …