Essential Role of Synoviolin in Embryogenesis

Yagishita, Naoko; Ohneda, Kinuko; Amano, Tetsuya; Yamasaki, Satoshi; Sugiura, Akiko; Tsuchimochi, Kaneyuki; Shin, Hiroshi; Kawahara, Kohichi; Onodera, Osamu; Ohta, Tomohiko; Tanaka, Sakae; Yamamoto, Masayuki; Maruyama, Ikuro; Nishioka, Kusuki; Fukamizu, Akiyoshi; Nakajima, Takeshi

doi:10.1074/jbc.m410863200

Cited by 94 publications

(95 citation statements)

References 43 publications

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“…HRD1 is part of a multiprotein complex that includes derlin, which has been reported to interact with torsinA (13). Hrd1-null mice exhibit embryonic lethality, and cells derived from these animals are more susceptible to ER stressinduced cell death (46), establishing a link between HRD1 function nia in humans. Mice modeling the dominant-negative action of the DYT1 mutation (N-SKI) feature a pattern of selective neuronal vulnerability and abnormal movements that emerge during postnatal CNS maturation, a picture broadly consistent with clinical features of the human disease.…”

Section: Discussionmentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA + ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a flox/-) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a flox/ΔE ) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a flox/ΔE compared with nestin-Cre Tor1a flox/-animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia. IntroductionThe primary dystonias, a group of sporadic and inherited illnesses, are a striking example of selective vulnerability of CNS sensorimotor circuits (1, 2). Dystonia -defined as prolonged, involuntary twisting movements -is traditionally classified as "primary" if it occurs in isolation and in the absence of neuropathological change. In contrast, "secondary" dystonic movements occur consequent to CNS damage (e.g., from stroke, trauma, or neurodegeneration), and are typically accompanied by additional neurological signs and symptoms. This classification scheme has been criticized (3), however, because neuroimaging of patients with primary dystonia indicates the presence of subtle neuropathological changes, and few primary dystonia brains have been comprehensively analyzed (4). Indeed, despite considerable interest in the pathophysiology of primary dystonia, the molecular and cellular underpinnings of CNS dysfunction and the identity of affected motor structures and cell types remain poorly understood. DYT1 dystonia is a common inherited form of primary dystonia that typically manifests during a discrete period of childhood, implicating abnormal development as the cause of motor dysfunction. This neurodevelopmental disease is caused by a 3 bp in-frame mutation in TOR1A that removes a single glutamic acid residue (ΔE) from the torsinA protein. TorsinA is a ubiquitously expressed AAA + protein residing in the lumen of the ER/nuclear envelope (ER/NE) space (5-7). Accumulating evidence indicates that the DYT1 mutation acts by impairing torsinA function through multiple mechan...

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Section: Discussionmentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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“…Hrd1 has an essential developmental role, and aberrant expression of Hrd1 has been associated with a number of chronic diseases (Amano et al 2003;Yagishita et al 2005;Hasegawa et al 2010). For instance, it was shown to be up-regulated in rheumatoid synovial cells, and overexpression of Hrd1 resulted in spontaneous arthropathy, whereas Hrd1 +/À mice were more resistant to collagen-induced arthritis (Amano et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

et al. 2014

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Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Downregulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

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“…Knockdown of Synoviolin increases p53 levels and p53 transcriptional activity promoting cell cycle arrest. Synoviolin deletion in mice causes embryonic death ;13.5 dpc, with apparent hypocellularity and aberrant apoptosis in fetal livers (Yagishita et al 2005). Definitive erythropoiesis is also affected in a non-cell-autonomous manner.…”

Section: Mdm2 Is Not Alonementioning

confidence: 99%

Limiting the power of p53 through the ubiquitin proteasome pathway

2014

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The ubiquitin proteasome pathway is critical in restraining the activities of the p53 tumor suppressor. Numerous E3 and E4 ligases regulate p53 levels. Additionally, deubquitinating enzymes that modify p53 directly or indirectly also impact p53 function. When alterations of these proteins result in increased p53 activity, cells arrest in the cell cycle, senesce, or apoptose. On the other hand, alterations that result in decreased p53 levels yield tumor-prone phenotypes. This review focuses on the physiological relevance of these important regulators of p53 and their therapeutic implications.

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Essential Role of Synoviolin in Embryogenesis

Cited by 94 publications

References 43 publications

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

Limiting the power of p53 through the ubiquitin proteasome pathway

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