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)

HtrA2/Omi is a mitochondrial serine protease that is released into the cytosol and promotes apoptotic processes by binding to several members of the inhibitors of apoptosis protein family. HtrA2/Omi knockout mice show a parkinsonian phenotype, and mutations in the gene encoding HtrA2/Omi have been identified as susceptibility factors for Parkinson disease (PD). These results suggest that HtrA2/Omi may be involved in the pathogenesis of PD. We performed immunohistochemical studies of HtrA2/Omi on brains from patients with alpha-synuclein-related disorders, including PD, dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA); patients with other neurodegenerative diseases; and controls. HtrA2/Omi is expressed in normal brain tissue, and there was some anti-HtrA2/Omi immunostaining of neurons in normal brains as well as those with other neurodegenerative diseases. In PD and DLB brains, both classic (i.e. brainstem-type) and cortical Lewy bodies were intensely immunostained; pale bodies were also strongly immunopositive for HtrA2/Omi. In MSA brains, numerous glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were also intensely immunoreactive for HtrA2/Omi. These results suggest that widespread accumulation of HtrA2/Omi may occur in pathologic alpha-synuclein-containing inclusions in brains with PD, DLB, or MSA and that HtrA2/Omi may be associated with the pathogenesis of alpha-synucleinopathies.
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PMID:Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. 1880 9

Parkinson's disease (PD) is a common neurodegenerative disorder. The motor neuron degeneration 2 mutant (mnd2) mouse exhibits loss of striatal neurons, muscle wasting, weight loss, and death within 40days of birth, and is considered to be a useful animal model of PD. mnd2 was identified as an autosomal recessive mutation in the HtrA2/Omi gene, which encodes a mitochondrial serine protease. Omi-deficient mitochondria are more sensitive to mitochondrial permeability transition (mPT), which raises the possibility that mPT plays a role in motor neurodegeneration in mnd2 mice. Given that cyclophilin D (CypD)-deficient mitochondria are resistant to mPT, we examined whether CypD-dependent mPT is involved in the pathogenesis of neurodegenerative disorders in mnd2 mice by generating CypD-deficient mnd2 mice. Brain mitochondria isolated from CypD-deficient mnd2 mice were more resistant to Ca(2+)-induced mPT than those of mnd2 mice. However, both mnd2 mice and CypD-deficient mnd2 mice showed similar survival periods and phenotypes, including the lack of weight gain, muscle wasting, and resting tremor. Our data suggest that CypD-dependent mPT does not play a major role in neurodegeneration in mnd2 mice.
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PMID:Cyclophilin D-dependent mitochondrial permeability transition is not involved in neurodegeneration in mnd2 mutant mice. 2012 86

Dopaminergic neurons in the substantia nigra are particularly vulnerable, and their degeneration leads to Parkinson's disease. We have previously reported that matrix metalloproteinase-3 (MMP-3) activity is involved in dopaminergic neurodegeneration by multiple mechanisms and that this requires activation of MMP-3 from proMMP-3 by an intracellular serine protease. HtrA2/Omi is a mitochondrial serine protease that has been shown in non-dopaminergic cells to translocate into the cytosol where it triggers apoptosis. In the present study we sought to determine whether HtrA2/Omi might cause activation of MMP-3 in dopaminergic neuronal cells using CATH.a cell line. Mitochondrial stress induced by rotenone led to MMP-3 activation and HtrA2/Omi translocation into the cytosol. The MMP-3 activation involved HtrA2/Omi, because both pharmacological inhibition and siRNA-induced knockdown of HtrA2/Omi attenuated the activation induced by rotenone or MPP+. Overexpression of mature HtrA2/Omi, but not mutant HtrA2/Omi, resulted in MMP-3 activity increase and cell death. Addition of recombinant and catalytically active HtrA2/Omi to lysate of untreated cells led to activation of the endogenous MMP-3, and incubation of the HtrA2/Omi with recombinant proMMP-3 caused cleavage of proMMP-3 to a 48kD protein, corresponding to the active form, which was accompanied by an increase in MMP-3 activity. Taken together, the data indicate that HtrA2/Omi, which normally exists in the mitochondria, can cause MMP-3 activation in the cytosol under a cell stress condition, which can ultimately lead to demise of dopaminergic neuronal cells.
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PMID:Matrix metalloproteinase-3 is activated by HtrA2/Omi in dopaminergic cells: relevance to Parkinson's disease. 2226 21

X-linked inhibitor of apoptosis protein (XIAP) blocks the apoptosis by binding to and inhibiting caspases-3, 7, and 9. XIAP is negatively regulated by the mitochondrial serine protease, HtrA2/Omi. The aim of this study was to investigate the role of XIAP and the relationship between XIAP and HtrA2/Omi in patients with Parkinson's disease or dementia with Lewy bodies. We conducted immunohistochemical studies on XIAP in formalin-fixed, paraffin-embedded sections from eight normal participants, 10 patients with Parkinson's disease, five patients with dementia with Lewy bodies, and seven patients with Alzheimer's disease, and then double-labeling immunohistochemistry for XIAP and HtrA2/Omi in sections from the Parkinson's disease and dementia with Lewy bodies cases. Brainstem-type and cortical Lewy bodies were intensely immunostained for XIAP, and XIAP immunoreactivity was localized to the halos of brainstem-type Lewy bodies and to the entire bodies of cortical Lewy bodies. Double immunofluorescence analyses showed that XIAP and HtrA2/Omi immunoreactivities were colocalized to both types of Lewy bodies. Our results suggest that XIAP may be partially associated with the pathogenesis of Parkinson's disease and dementia with Lewy bodies.
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PMID:Immunohistochemical localization of X-linked inhibitor of apoptosis protein in brainstem-type and cortical Lewy bodies. 2227 71

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.
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PMID:Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease. 2582 81

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Mutations in the DJ-1, including L166P, are responsible for recessive early-onset PD. Many lines of evidence have shown that L166P is not only a loss-of-function mutant, but also a pro-apoptotic-like protein that results in mitochondrial dysfunction. L166P has been reported to be unstable and to mislocalize to mitochondria. However, the mechanisms underlying the instability of L166P compared to wild-type DJ-1 remain largely unknown. Here, we showed that Omi/HtrA2, a mitochondrial serine protease that has also been linked to the pathogenesis of PD, contributed to L166P instability. Omi directly interacted with and cleaved L166P in mitochondria to decrease the L166P level. However, Omi did not bind and cleave wild-type DJ-1. Moreover, Omi cleaved L166P at both serine residues 3 and 121, while L166P-induced cell death under H2O2 treatment was alleviated by over-expression of Omi. Our data reveal a bridge between DJ-1 and Omi, two PD-associated genetic factors, which contributes to our understanding of the pathogenesis of PD.
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PMID:Familial Parkinson's Disease-Associated L166P Mutant DJ-1 is Cleaved by Mitochondrial Serine Protease Omi/HtrA2. 2917 68

Activation of the inflammasome pathway is crucial for effective intracellular host defense. The mitochondrial network plays an important role in inflammasome regulation but the mechanisms linking mitochondrial homeostasis to attenuation of inflammasome activation are not fully understood. Here, we report that the Parkinson's disease-associated mitochondrial serine protease HtrA2 restricts the activation of ASC-dependent NLRP3 and AIM2 inflammasomes, in a protease activity-dependent manner. Consistently, disruption of the protease activity of HtrA2 results in exacerbated NLRP3 and AIM2 inflammasome responses in macrophages ex vivo and systemically in vivo. Mechanistically, we show that the HtrA2 protease activity regulates autophagy and controls the magnitude and duration of inflammasome signaling by preventing prolonged accumulation of the inflammasome adaptor ASC. Our findings identify HtrA2 as a non-redundant mitochondrial quality control effector that keeps NLRP3 and AIM2 inflammasomes in check.
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PMID:The mitochondrial protease HtrA2 restricts the NLRP3 and AIM2 inflammasomes. 2985 23