Abstract
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.
Highlights
FUS-proteinopathies are a group of genetically and clinically heterogeneous diseases that manifest in different manners depending on the region affected, such as motor neuron diseases (ALS-FUS) or various forms of dementia, including frontotemporal lobar degeneration with FUS pathology (FTLD-FUS), atypical FTLD with ubiquitin pathology, and other distinct forms of FTLD such as neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD)[1]
Male and female human FUS (hFUS)-expressing flies at 25 °C showed an area of degeneration with fused ommatidia only 6 days after eclosion, while an aberrant eye structure was clearly detected in 1-day-old adult flies developed at 28 °C
The main aim of the present study was to investigate the eventual role of long non-coding RNAs (lncRNAs) in the pathomechanisms of FUS-proteinopathies. lncRNAs, which are a class of transcripts longer than 200 nucleotides with no or very low coding potential[47] and similar to mRNA, but with proper specific features[48], are predicted to function, often preferentially, in the nervous system, in which they may play roles in mediating neuronal development, behavior, and cognitive functions
Summary
FUS-proteinopathies are a group of genetically and clinically heterogeneous diseases that manifest in different manners depending on the region affected, such as motor neuron diseases (ALS-FUS) or various forms of dementia, including frontotemporal lobar degeneration with FUS pathology (FTLD-FUS), atypical FTLD with ubiquitin pathology (aFTLD-U), and other distinct forms of FTLD such as neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD)[1]. Heterologous expression in the fly revealed that hFUS has the ability to translocate to mitochondria through the mediation of Hsp[60] and induces apoptosis as a consequence of mitochondrial damage[17]. This recent finding showed that in the absence of mutations, higher FUS levels represent a critical event in FUS-proteinopathies. FUS preferentially binds to long transcripts, and previous studies highlighted its ability to control a large number of long non-coding RNAs (lncRNAs) with important functions at different levels in the central nervous system (CNS)[27]. An increasing number of studies have clearly revealed the important role of lncRNAs in many neurological diseases, it has not yet been established whether they play a role in the pathogenesis of FUS-proteinopathies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
