Last update 01 Nov 2024

ZC3H14

Last update 01 Nov 2024

Basic Info

Synonyms

FLJ11806, Mammalian suppressor of tau pathology-2, MSUT-2

+ [6]

Introduction

Involved in poly(A) tail length control in neuronal cells. Binds the polyadenosine RNA oligonucleotides.

100 Clinical Results associated with ZC3H14

100 Translational Medicine associated with ZC3H14

0 Patents (Medical) associated with ZC3H14

Literatures (Medical) associated with ZC3H14

01 Aug 2024·Molecular Biology of the Cell

The RNA-binding protein Nab2 regulates levels of the RhoGEF Trio to govern axon and dendrite morphology

Article

Author: Lancaster, Carly L ; Leung, Sara W ; Corbett, Anita H ; Yalamanchili, Pranav S ; Moberg, Kenneth H ; Goldy, Jordan N

The Drosophila RNA-binding protein (RBP) Nab2 acts in neurons to regulate neurodevelopment and is orthologous to the human intellectual disability-linked RBP, ZC3H14. Nab2 governs axon projection in mushroom body neurons and limits dendritic arborization of class IV sensory neurons in part by regulating splicing events in ∼150 mRNAs. Analysis of the Sex-lethal ( Sxl) mRNA revealed that Nab2 promotes an exon-skipping event and regulates m6A methylation on Sxl pre-mRNA by the Mettl3 methyltransferase. Mettl3 heterozygosity broadly rescues Nab2null phenotypes implying that Nab2 acts through similar mechanisms on other RNAs, including unidentified targets involved in neurodevelopment. Here, we show that Nab2 and Mettl3 regulate the removal of a 5′UTR (untranslated region) intron in the trio pre-mRNA. Trio utilizes two GEF domains to balance Rac and RhoGTPase activity. Intriguingly, an isoform of Trio containing only the RhoGEF domain, GEF2, is depleted in Nab2null nervous tissue. Expression of Trio-GEF2 rescues projection defects in Nab2null axons and dendrites, while the GEF1 Rac1-regulatory domain exacerbates these defects, suggesting Nab2-mediated regulation Trio-GEF activities. Collectively, these data indicate that Nab2-regulated processing of trio is critical for balancing Trio-GEF1 and -GEF2 activity and show that Nab2, Mettl3, and Trio function in a common pathway that shapes axon and dendrite morphology.

01 Jun 2024·Acta Neuropathologica

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons

Article

Author: Luk, Kelvin C ; Kraemer, Brian ; Xu, Hong ; Qiu, Qi ; Trojanowski, John Q ; Wu, Hao ; Lee, Edward B ; Hu, Peng ; Kim, Christopher ; He, Zhuohao ; Zhang, Bin ; Hoxha, Kevt'her ; O'Reilly, Mia ; Changolkar, Lakshmi ; Marotta, Nicholas ; Brunden, Kurt R ; Schellenberg, Gerard D ; Jang, Elliot ; Lee, Virginia M-Y

AbstractInclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer’s disease (AD). The spreading of misfolded tau “seeds” along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the “ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein” (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.

01 Sep 2023·Journal of applied genetics

Congenital coenzyme Q5-linked pathology: causal genetic association, core phenotype, and molecular mechanism.

Article

Author: Goszczanska-Ciuchta, Alicja ; Wiszniewski, Wojciech ; Jurek, Marta ; Gawlinski, Pawel ; Bukowska-Olech, Ewelina ; Guilbride, Dorothy Lys ; Bekiesinska-Figatowska, Monika ; Podwysocka, Aleksandra ; Rygiel, Agnieszka Magdalena ; Dawidziuk, Mateusz ; Obersztyn, Ewa

Coenzyme Q5 (COQ5), a C-methyltransferase, modifies coenzyme Q10 (COQ10) during biosynthesis and interacts with polyA-tail regulating zinc-finger protein ZC3H14 in neural development. Here, we present a fifth patient (a third family) worldwide with neurodevelopmental and physiological symptoms including COQ10 deficiency. Our patient harbors one novel c.681+1G>A and one recurrent p.Gly118Ser variant within COQ5. The patient's mRNA profile reveals multiple COQ5 splice-variants. Subsequently, we comprehensively described patient's clinical features as compared to phenotype and symptoms of other known congenital coenzyme Q5-linked cases. A core spectrum of COQ5-associated symptoms includes reduced COQ10 levels, intellectual disability, encephalopathy, cerebellar ataxia, cerebellar atrophy speech regression/dysarthria, short stature, and developmental delays. Our patient additionally displays dysmorphia, microcephaly, and regressive social faculties. These results formally establish causal association of biallelic COQ5 mutation with pathology, outline a core COQ5-linked phenotype, and identify mRNA mis-splicing as the molecular mechanism underlying all COQ5 variant-linked pathology to date.

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ZC3H14

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