ISWI ATP-dependent remodeling of nucleoplasmic ω-speckles in the brain of Drosophila melanogaster

Bonaccorso

Attardi

et al. 2018

IJMS

Self Cite

Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human TAR DNA-binding 43 protein (TDP-43) from the nucleus to cytoplasmic inclusions is a pathological feature of several diseases. Indeed, sporadic and familial forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration share as hallmarks ubiquitin-positive inclusions. Recently, the wide spectrum of neurodegenerative diseases characterized by RBPs functions’ alteration and loss was collectively named proteinopathies. Here, we show that TBPH (TAR DNA-binding protein-43 homolog), the Drosophila ortholog of human TDP-43 TAR DNA-binding protein-43, interacts with the arcRNA hsrω and with hsrω-associated hnRNPs. Additionally, we found that the loss of the omega speckles remodeler ISWI (Imitation SWI) changes the TBPH sub-cellular localization to drive a TBPH cytoplasmic accumulation. Our results, hence, identify TBPH as a new component of omega speckles and highlight a role of chromatin remodelers in hnRNPs nuclear compartmentalization.

Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 62%

Loss of ISWI Function in Drosophila Nuclear Bodies Drives Cytoplasmic Redistribution of Drosophila TDP-43

Bonaccorso

Attardi

et al. 2018

IJMS

Self Cite

“…Further experiments are required to extend the knowledge in this regard. Notably, we herein did not examine whether hsrω indirectly affects FUS through the activity of other hnRNPs, which is possible because defects in the lncRNA hsrω alter compartmentalization 53 , 54 and the functions 55 of diverse hnRNPs that, in turn, have roles in RNA processing 56 .…”

Section: Discussionmentioning

confidence: 99%

FUS toxicity is rescued by the modulation of lncRNA hsrω expression in Drosophila melanogaster

Jantrapirom

Nagai

et al. 2017

Sci Rep

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FUS is an aggregation-prone hnRNP involved in transcriptional and post-transcriptional regulation that aberrantly forms immunoreactive inclusion bodies in a range of neurological diseases classified as FUS-proteinopathies. Although FUS has been extensively examined, the underlying molecular mechanisms of these diseases have not yet been elucidated in detail. We previously reported that RNAi of the lncRNA hsrω altered the expression and sub-cellular localization of Drosophila FUS in the central nervous system of the fly. In order to obtain a clearer understanding of the role of hsrω in FUS toxicity, we herein drove the expression of human FUS in Drosophila eyes with and without a hsrω RNAi background. We found that hFUS was largely soluble and also able to form aggregates. As such, hFUS was toxic, inducing an aberrant eye morphology with the loss of pigmentation. The co-expression of hsrω double-stranded RNA reduced hFUS transcript levels and induced the formation of cytoplasmic non-toxic hFUS-LAMP1-insoluble inclusions. The combination of these events caused the titration of hFUS molar excess and a removal of hFUS aggregates to rescue toxicity. These results revealed the presence of a lncRNA-dependent pathway involved in the management of aggregation-prone hnRNPs, suggesting that properly formed FUS inclusions are not toxic to cells.

“…The lncRNA hsrω is known to interact with and organize several RBPs like the Drosophila FUS (Cabeza), TDP-43 (TBPH), hnRNPAB (Squid) and hnRNPA2B1 (Hrb87F) to form the ω-speckles, a specialized nuclear compartment that is functionally important; flies that are null for both copies of hsrω exhibit severe dysfunctions in RNA processing and chromatin structure, which causes lethality (Jolly and Lakhotia, 2006; Lakhotia and Sharma, 1996; Lo Piccolo et al, 2017a, 2018; Ray et al, 2019; Ray and Lakhotia, 1998). Together, with such a critical structural role, hsrω also regulates the activity of a large variety of proteins, including the histone acetyltransferase CBP, the chromatin remodeler ISWI and heterochromatin protein 1 (HP1) (Lakhotia et al, 2012; Mallik and Lakhotia, 2010; Onorati et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The lncRNA hsrω regulates arginine dimethylation of human FUS to cause its proteasomal degradation in Drosophila

Journal of Cell Science

Mochizuki

Nagai

2019

Self Cite

Long non-coding RNAs (lncRNAs) have structural and regulatory effects on RNA-binding proteins (RBPs). However, the mechanisms by which lncRNAs regulate the neurodegenerative-causative RBP like FUS protein remain poorly understood. Here, we show that knockdown of the Drosophila lncRNA hsrω causes a shift in the methylation status of human FUS from mono- (MMA) to di-methylated (DMA) arginine via upregulation of the arginine methyltransferase 5 (PRMT5, known as ART5 in flies). We found this novel regulatory role to be critical for FUS toxicity since the PRMT5-dependent dimethylation of FUS is required for its proteasomal degradation and causes a reduction of high levels of FUS. Moreover, we show that an increase of FUS causes a decline of both PRMT1 (known as ART1 in flies) and PRMT5 transcripts, leading to an accumulation of neurotoxic MMA-FUS. Therefore, overexpression of either PRMT1 or PRMT5 is able to rescue the FUS toxicity. These results highlight a novel role of lncRNAs in post-translation modification (PTM) of FUS and suggest a causal relationship between lncRNAs and dysfunctional PRMTs in the pathogenesis of FUSopathies.