Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet
ABSTRACT 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.
- SourceAvailable from: Dwaipayan Sen
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- "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). "
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.Acta neurobiologiae experimentalis 04/2015; 75:1-26. · 2.24 Impact Factor
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- "fungicides, herbicides, pesticides, and metals  . Mutations in a number of genes are associated with both familial and sporadic forms of PD, including alpha-synuclein, Parkin and many others    . 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. "
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.CNS & neurological disorders drug targets 07/2013; 13(1). DOI:10.2174/18715273113129990082 · 2.70 Impact Factor
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- "A major advance occurred in a recent study in which researchers identified disease-causing PINK1 mutations in familial PD . Mutations in the mitochondrial serine protease HTRA2 were also reported to be associated with PD in sporadic patients ; however, the role of HTRA2 in PD remains controversial  "
ABSTRACT: Mitochondria are cellular energy generators whose activity requires a continuous supply of oxygen. Recent genetic analysis has suggested that defects in mitochondrial quality control may be key factors in the development of Parkinson's disease (PD). Mitochondria have a crucial role in supplying energy to the brain, and their deterioration can affect the function and viability of neurons, contributing to neurodegeneration. These organelles can sow the seeds of their own demise because they generate damaging oxygen-free radicals as a byproduct of their intrinsic physiological functions. Mitochondria have therefore evolved specific molecular quality control mechanisms to compensate for the action of damaging agents such as oxygen-free radicals. PTEN-induced putative kinase 1 (PINK1) and high-temperature-regulated A2 (HTRA2), a mitochondrial protease, have recently been proposed to be key modulators of mitochondrial molecular quality control. Here, we review some of the most recent advances in our understanding of mitochondria stress-control pathways, focusing on how signalling by the p38 stress kinase pathway may regulate mitochondrial stress by modulating the activity of HTRA2 via PINK1 and cyclin-dependent kinase 5 (CDK5). We also propose how defects in this pathway may contribute to PD.International Journal of Cell Biology 05/2012; 2012:607929. DOI:10.1155/2012/607929