Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.
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PMID:Expanding insights of mitochondrial dysfunction in Parkinson's disease. 1649 42

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.
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PMID:Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria? 1768 Aug 6

Studies of familial forms of Parkinson's disease (PD) have identified a growing number of genes that derive from the loci given the nomenclature PARK1-PARK13 (OMIM 168600). The alpha-synuclein gene has been implicated in rare autosomal dominant PD because of either mis-sense mutations (PARK1) or gene multiplications (PARK4). Moreover, UCHL1 (PARK5), LRRK2 (PARK8) and HTRA2 (PARK13) have been identified as causative genes for autosomal dominant PD, whereas parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and ATP13A2 (PARK9) have been identified as causative genes for autosomal recessive PD. Neuropathological examination of the kindreds of PARK1/4 showed Lewy body pathology ranging from classic PD to diffuse Lewy body disease. The pathological findings of PARK3 are similar to those of classic PD. In contrast, autopsies of patients with PARK2 showed nigral cell loss without Lewy bodies, although exceptions have been reported. Several kindreds of PARK8 included cases with Lewy body pathology, tau pathology, or with nigral cell loss in the absence of obvious protein deposition. Ubiquitin-positive inclusions that are negative for alpha-synuclein and tau are also seen in some cases. Moreover, widespread Lewy body pathology was also reported in several cases of familial Alzheimer's disease with presenilin-1 mutations.
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PMID:[Pathology of familial Parkinson's disease]. 1771 21

In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.
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PMID:The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. 1797 47

alpha-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration. Using old yeast as a model of alpha-synuclein expression in post-mitotic cells, we show that alpha-synuclein toxicity depends on chronological aging and results in apoptosis as well as necrosis. Neither disruption of key components of the unfolded protein response nor deletion of proapoptotic key players (including the yeast caspase YCA1, the apoptosis-inducing factor AIF1, or the serine protease OMI) did prevent alpha-synuclein-induced cell killing. However, abrogation of mitochondrial DNA (rho(0)) inhibited alpha-synuclein-induced reactive oxygen species formation and subsequent apoptotic cell death. Thus, introducing an aging yeast model of alpha-synuclein toxicity, we demonstrate a strict requirement of functional mitochondria.
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PMID:Functional mitochondria are required for alpha-synuclein toxicity in aging yeast. 1819 73

A novel heterozygous non-synonymous mutation and a novel polymorphism in OMI/HTRA2 locus have been associated with Parkinson's disease (PD) in a German population. In an attempt to replicate these results in an independent population, we analyzed the entire coding region of OMI/HTRA2 in a series of 644 North American PD cases with both young- and late-onset disease and in 828 North American neurologically normal controls. Our results show that neither of the variants previously related to PD were associated with PD in our cohort and that the risk variants were present in neurologically normal controls.
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PMID:Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. 1836 87

Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.
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PMID:Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. 1902 30

Parkinson's disease (PD) is a common, disabling, neurodegenerative disease. Our knowledge of the molecular events leading to PD is being greatly enhanced by the study of relatively rare familial form of the disease. Nevertheless, the pathways leading from the genetic mutations to nigral cell degeneration and the other features in PD remain poorly understood. The identification of PINK1, a mitochondrial putative protein kinase, has helped understand the pathophysiology of mitochondria and their potential role in PD. Mutations in PINK1 are associated with the PARK6 autosomal recessive, early-onset, PD-susceptibility locus. Point mutations in another mitochondrial protein, HtrA2, are a susceptibility factor for PD (PARK13 locus). We report here the results of investigations into the interactors and pathways of these two mitochondrial molecules (PINK1 and HtrA2) in a range of models and human PD tissue.
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PMID:What have PINK1 and HtrA2 genes told us about the role of mitochondria in Parkinson's disease? 1907 28

Recent whole genome association studies provided little evidence that polymorphisms at the familial Parkinsonism loci influence the risk for Parkinson's disease (PD). However, these studies are not designed to detect the types of subtle effects that common variants may impose. Here, we use an alternative targeted candidate gene approach to examine common variation in 11 genes related to familial Parkinsonism. PD cases (n = 331) and unaffected control subjects (n = 296) were recruited from three specialist movement disorder clinics in Brisbane, Australia and the Australian Electoral Roll. Common genetic variables (76 SNPs and 1 STR) were assessed in all subjects and haplotype, genotype, and allele associations explored. Modest associations (uncorrected P < 0.05) were observed for common variants around SNCA, UCHL1, MAPT, and LRRK2 although none were of sufficient magnitude to survive strict statistical corrections for multiple comparisons. No associations were seen for PRKN, PINK1, GBA, ATP13A2, HTRA2, NR4A2, and DJ1. Our findings suggest that common genetic variables of selected PD-related loci contribute modestly to PD risk in Australians.
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PMID:Do polymorphisms in the familial Parkinsonism genes contribute to risk for sporadic Parkinson's disease? 1922 17

High temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that exhibits proapoptotic and cell-protective properties and has been linked to Parkinson's disease (PD). Impaired mitochondrial function is a common trait in PD patients, and is likely to play a significant role in pathogenesis of parkinsonism, but the molecular mechanisms remain poorly understood. Genetic studies in Drosophila have provided valuable insight into the function of other PD-linked genes, in particular PINK1 and parkin, and their role in maintaining mitochondrial integrity. Recently, HtrA2 was shown to be phosphorylated in a PINK1-dependent manner, suggesting it might act in the PINK1 pathway. Here, we describe the characterization of mutations in Drosophila HtrA2, and genetic analysis of its function with PINK1 and parkin. Interestingly, we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis. In addition, we found HtrA2 mutants share some phenotypic similarities with parkin and PINK1 mutants, suggesting that it may function in maintaining mitochondrial integrity. Our genetic interaction studies, including analysis of double-mutant combinations and epistasis experiments, suggest HtrA2 acts downstream of PINK1 but in a pathway parallel to Parkin.
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PMID:Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. 1928 69


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