Abstract
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.
Highlights
In the past year, several studies have indicated that heterogeneous ribonucleoprotein are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and fronto-temporal lobar degeneration (FTLD)
We conducted double-immunofluorescence for TBPH/Hrb87F and TBPH/Squid and, as shown in Figure 1, we found that TBPH co-localizes in Malpighian tubules (MT) with Squid (Figure 1A–C) and Hrb87F hnRNPs in vivo ( Figure 1D–F and Figure S1)
Several in vitro experiments through proteomic studies [14,34] and co-immunoprecipitation assay in HEK293 cells [35] showed that in human cells TAR DNA-binding protein 43 (TDP-43) interacts with the Drosophila orthologs of Squid and Hrb87F hnRNPs
Summary
Several studies have indicated that heterogeneous ribonucleoprotein (hnRNPs) are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and fronto-temporal lobar degeneration (FTLD). These conditions share the presence of cytoplasmic or nuclear aggregates of RNA-binding proteins (RBPs) and RNA [1,2,3,4,5,6,7,8]. TDP-43 regulates synaptic plasticity by governing the transport and splicing of synaptic mRNAs [13] and it is involved in different important functions that regulate RNA metabolism as well as transcriptional repression, exon skipping, RNA splicing and transport/stability, microRNA expression, and RNA translation [14,15,16,17]
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