Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease

ArticleinHuman Molecular Genetics 14(15):2099-111 · September 2005with57 Reads
DOI: 10.1093/hmg/ddi215 · Source: PubMed
Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.


    • "It is released from mitochondria to cytosol to cleave XIAP in response to apoptotic stimuli, which induces apoptosis [94]. In 2005, it was found that loss of OMI protease activity is associated with PD [95]. mnd2 (motor neuron degeneration 2) mice which harbor protease-deficient OMI S276C mutants, and OMI-knockout mice present motor abnormalities similar to PD, with the progressive neurodegeneration in some brain regions, especially in striatum [96]. "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.
    Full-text · Article · Dec 2016
    • "The activity of HTRA2/OMI is regulated by phosphorylation by PINK1 (Plun-Favreau et al. 2007). Finally, loss-of-function mutations in OMI/HTRA2 have been associated with PD incidence in a human population (Strauss et al. 2005). Interestingly mutations in the MT folding chaperone HSP70 also associate with PD and expression of these mutant alleles affect MT function in cell models (Fig. 4) (Burbulla et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson’s disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson’s disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson’s disease leading to neurodegeneration.
    Full-text · Article · Apr 2015
    • "fungicides, herbicides, pesticides, and metals [1] [2]. Mutations in a number of genes are associated with both familial and sporadic forms of PD, including alpha-synuclein, Parkin and many others [3] [4] [5] [6]. How such environmental and genetic risk factors drive the etiological and biological underpinnings of PD, such as oxidative and nitrosative stress (O&NS), mitochondrial dysfunction, peripheral and central inflammation, as well as immune driven changes awaits clarification. "
    [Show abstract] [Hide abstract] ABSTRACT: Increased depression, somatization, gut inflammation and wider peripheral inflammation are all associated with the early stages of Parkinson's disease (PD). Classically such concurrent conditions have been viewed as "comorbidities", driven by high levels of stress in a still poorly understood and treated disorder. Here we review the data on how oxidative and nitrosative stress in association with immuno-inflammatory responses, drives alteration in tryptophan catabolites, including kynurenine, kynurenic acid and quinolinic acid that drive not only the "comorbidities" of PD but also important processes in the etiology and course of PD per se. The induction of indoleamine 2,3-dioxygenase, leading to the driving of tryptophan into neuroregulatory tryptophan catabolite products and away from serotonin and melatonin production, has significant implications for understanding the role of nicotine, melatonin, and caffeine in regulating PD susceptibility. Tryptophan catabolite pathway activation will also regulate blood-brain barrier permeability, glia and mast cell reactivity as well as wider innate and adaptive immune cell responses, all relevant to the course of PD. As such, the "comorbidities" of PD such as depression, somatization and peripheral inflammatory disorders can all be conceptualized as being an intricate part of the biological underpinnings of both the etiology and course of PD. As a consequence, the data reviewed here has treatment implications; relevant to both the course of PD and in the management of L-DOPA induced dyskinesias.
    Full-text · Article · Jul 2013
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