Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease

Abstract Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primaril...

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Autores principales:	Yutaro Obara, Toru Imai, Hidenori Sato, Yuji Takeda, Takeo Kato, Kuniaki Ishii
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b0a473ce608c4da7bb4b61ac2a2f43c5
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spelling	oai:doaj.org-article:b0a473ce608c4da7bb4b61ac2a2f43c52021-12-02T11:53:11ZMidnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease10.1038/s41598-017-05456-02045-2322https://doaj.org/article/b0a473ce608c4da7bb4b61ac2a2f43c52017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05456-0https://doaj.org/toc/2045-2322Abstract Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primarily to the nucleus and intracellular membranes. Nerve growth factor promoted MIDN gene expression, which was attenuated by specific inhibitors of extracellular signal-regulated kinases 1/2 and 5. MIDN-deficient PC12 cells created using CRISPR/Cas9 technology displayed significantly impaired neurite outgrowth. Interestingly, a genetic approach revealed that 10.5% of patients with sporadic Parkinson’s disease (PD) had a lower MIDN gene copy number whereas no copy number variation was observed in healthy people, suggesting that MIDN is involved in PD pathogenesis. Furthermore, the expression of parkin, a major causative gene in PD, was significantly reduced by CRISPR/Cas9 knockout and siRNA knockdown of MIDN. Activating transcription factor 4 (ATF4) was also down-regulated, which binds to the cAMP response element (CRE) in the parkin core promoter region. The activity of CRE was reduced following MIDN loss. Overall, our data suggests that MIDN promotes the expression of parkin E3 ubiquitin ligase, and that MIDN loss can trigger PD-related pathogenic mechanisms.Yutaro ObaraToru ImaiHidenori SatoYuji TakedaTakeo KatoKuniaki IshiiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yutaro Obara Toru Imai Hidenori Sato Yuji Takeda Takeo Kato Kuniaki Ishii Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
description	Abstract Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primarily to the nucleus and intracellular membranes. Nerve growth factor promoted MIDN gene expression, which was attenuated by specific inhibitors of extracellular signal-regulated kinases 1/2 and 5. MIDN-deficient PC12 cells created using CRISPR/Cas9 technology displayed significantly impaired neurite outgrowth. Interestingly, a genetic approach revealed that 10.5% of patients with sporadic Parkinson’s disease (PD) had a lower MIDN gene copy number whereas no copy number variation was observed in healthy people, suggesting that MIDN is involved in PD pathogenesis. Furthermore, the expression of parkin, a major causative gene in PD, was significantly reduced by CRISPR/Cas9 knockout and siRNA knockdown of MIDN. Activating transcription factor 4 (ATF4) was also down-regulated, which binds to the cAMP response element (CRE) in the parkin core promoter region. The activity of CRE was reduced following MIDN loss. Overall, our data suggests that MIDN promotes the expression of parkin E3 ubiquitin ligase, and that MIDN loss can trigger PD-related pathogenic mechanisms.
format	article
author	Yutaro Obara Toru Imai Hidenori Sato Yuji Takeda Takeo Kato Kuniaki Ishii
author_facet	Yutaro Obara Toru Imai Hidenori Sato Yuji Takeda Takeo Kato Kuniaki Ishii
author_sort	Yutaro Obara
title	Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
title_short	Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
title_full	Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
title_fullStr	Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
title_full_unstemmed	Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease
title_sort	midnolin is a novel regulator of parkin expression and is associated with parkinson’s disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b0a473ce608c4da7bb4b61ac2a2f43c5
work_keys_str_mv	AT yutaroobara midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease AT toruimai midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease AT hidenorisato midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease AT yujitakeda midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease AT takeokato midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease AT kuniakiishii midnolinisanovelregulatorofparkinexpressionandisassociatedwithparkinsonsdisease
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Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease

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