Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1

Shiga, Atsushi; Nozaki, Hiroaki; Yokoseki, Akio; Nihonmatsu, Megumi; Kawata, Hirotoshi; Kato, Taisuke; Koyama, Akira; Arima, Kunimasa; Ikeda, Mari; Katada, Shinichi; Toyoshima, Yasuko; Takahashi, Hitoshi; Tanaka, Akira; Nakano, Imaharu; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Onodera, Osamu

doi:10.1093/hmg/ddr063

Cited by 95 publications

(94 citation statements)

References 35 publications

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“…Among 15 NMD-related factors, we identified that SMG-8 can suppress NMD efficiently with minimum cytotoxic effects. The ability of SMG-8 knockdown to efficiently suppress NMD was confirmed using another PTC-containing cell line from a patient with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (12,30).…”

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confidence: 84%

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Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

Usuki

Yamashita

Shiraishi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI α 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cellcycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases.therapy | genetic disorder with premature termination codon | siRNA

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confidence: 84%

“…However, if NMD degrades aberrant proteins that retain some normal cell function, disease conditions are exacerbated. There are many examples of mutant proteins that are degraded by NMD that retain some residual activity and partially normal function, resulting in an exacerbation of the defects caused by the original mutation (10)(11)(12)(13).…”

mentioning

confidence: 99%

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

Usuki

Yamashita

Shiraishi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This led the authors to propose the lack of TGF-processing as a critical disease mechanism. 101 Contrasting these findings, a more recent study in HTRA1-deficient mice and CARASIL patient cells revealed a facilitating role of HtrA1 on the TGF-pathway. 35 The same study showed that LTBP-1 is a substrate for HtrA1.…”

Section: Cerebral Autosomal Recessive Arteriopathy With Subcortical Imentioning

confidence: 96%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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“…This mechanism regulates the amount of mature TGF-"1. 24 No disease-specific therapy for CARASIL is available at this time.…”

Section: Cerebral Autosomal Dominantmentioning

confidence: 99%

Genetic Stroke Syndromes

Barrett¹,

Meschia²

2014

CONTINUUM: Lifelong Learning in Neurology

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Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1

Cited by 95 publications

References 35 publications

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Genetic Stroke Syndromes

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