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

Strauss, Karsten M.; Martins, L. Miguel; Plun‐Favreau, Hélène; Marx, Frank P.; Kautzmann, Sabine; Berg, Daniela; Gasser, Thomas; Wszolek, Zbginiew; Müller, Thomas; Bornemann, Antje; Wolburg, Hartwig; Downward, Julian; Rieß, Olaf; Schulz, Jörg B.; Krüger, Rejko

doi:10.1093/hmg/ddi215

Cited by 508 publications

(400 citation statements)

References 30 publications

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“…7 Missense mutations in the gene coding for Omi were reported to be associated with Parkinson's disease (PD). 8 In agreement with these findings, accumulation of Omi was found in neuronal and glial inclusions in brains with a-synucleinopathies, 9 as well as in Lewy bodies. 8 Omi knockout (KO) mice suffered the loss of a population of neurons in the striatum, which resulted in a neurodegenerative disorder with a PD phenotype.…”

supporting

confidence: 75%

“…8 In agreement with these findings, accumulation of Omi was found in neuronal and glial inclusions in brains with a-synucleinopathies, 9 as well as in Lewy bodies. 8 Omi knockout (KO) mice suffered the loss of a population of neurons in the striatum, which resulted in a neurodegenerative disorder with a PD phenotype. These mice died within 30 days after birth, similarly to mnd2 mice.…”

supporting

confidence: 75%

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Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Wang

et al. 2010

Cell Death Differ

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Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases.

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supporting

confidence: 75%

supporting

confidence: 75%

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Wang

et al. 2010

Cell Death Differ

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“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

Section: Genes and Loci In Familial Pdmentioning

confidence: 99%

“…A German study screened PD cases for mutations in the Omi/HtrA2 gene because Omi/HtrA2 is associated with a parkinsonian phenotype in mice [182]. One heterozygous mutation was detected in four of 518 PD cases, and in vitro studies indicated that the mutation resulted in impaired protein function.…”

Section: Park13mentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…Moreover, both Omi-knockout mice and mnd2 (motor neuron degeneration 2) mice, which harbor a protease-deficient Omi S276C mutant, exhibited an early onset neurodegeneration and motor abnormalities similar to Parkinson's disease (PD) [9,10] . Missense mutations that lead to a loss of Omi protease activity have been associated with PD [11,12] . These studies suggest that intact Omi protease activity is necessary for neuronal function and survival.…”

Section: Introductionmentioning

confidence: 99%

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

et al. 2015

Acta Pharmacol Sin

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Aim:Omi is an ATP-independent serine protease that is necessary for neuronal function and survival. The aim of this study was to investigate the role of protease Omi in regulating differentiation of mouse neuroblastoma cells and to identify the substrate of Omi involved in this process. Methods: Mouse neuroblastoma N2a cells and Omi protease-deficient mnd2 mice were used in this study. To modulate Omi and E2F1 expression, N2a cells were transfected with expression plasmids, shRNA plasmids or siRNA. Protein levels were detected using immunoblot assays. The interaction between Omi and E2F1 was studied using immunoprecipitation, GST pulldown and in vitro cleavage assays. N2a cells were treated with 20 μmol/L retinoic acid (RA) and 1% fetal bovine serum to induce neurite outgrowth, which was measured using Image J software. Results: E2F1 was significantly increased in Omi knockdown cells and in brain lysates of mnd2 mice, and was decreased in cells overexpressing wild-type Omi, but not inactive Omi S276C. In brain lysates of mnd2 mice, endogenous E2F1 was co-immunoprecipitated with endogenous Omi. In vitro cleavage assay demonstrated that Omi directly cleaved E2F1. Treatment of N2a cells with RA induced marked differentiation and neurite outgrowth accompanied by significantly increased Omi and decreased E2F1 levels, which were suppressed by pretreatment with the specific Omi inhibitor UCF-101. Knockdown of Omi in N2a cells suppressed RA-induced neurite outgrowth, which was partially restored by knockdown of E2F1. Conclusion: Protease Omi facilitates neurite outgrowth by cleaving the transcription factor E2F1 in differentiated neuroblastoma cells; E2F1 is a substrate of Omi.

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

Cited by 508 publications

References 30 publications

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

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