Specific RNA Alterations Key in ALS, Study Suggests

Specific alterations in RNA processing are molecular hallmarks of familial and sporadic forms of amyotrophic lateral sclerosis (ALS), a new study suggests. This research might lead to more discoveries  about how ALS develops and ultimately contribute to a cure.

The study, “Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS,” was published in the journal Nature Communications.

RNA is the molecule between DNA and a protein. The information in a gene (DNA) is transcribed into a RNA molecule that then is translated into a protein.

ALS-causing mutations implicate key regulators of RNA processing, raising the possibility that changes occurring after the conversion from DNA to RNA may play a role in development of the disease.

Mechanisms of RNA processing are critical for development and proper functioning of neurons. One of these mechanisms is intron retention (IR), which is characterized by the inclusion of introns in mature RNA molecules.

Unlike exons, which contain the genetic information to produce proteins, introns are normally taken out before RNA is translated to proteins.

Alternative polyadenylation (APA) is another form of RNA processing consisting in the generation of different lengths in RNA molecules, at regions not translated to proteins. However, these so-called 3’ untranslated regions (3’ UTRs) control the efficiency through which RNA is translated to proteins, its localization and stability.

Despite these findings, the roles of IR and 3′ UTR regulation in the development and homoeostasis of motor neurons – specialized neurons extending from the central nervous system to muscles and degenerated in ALS – have remained unclear.

Both AS and APA are coordinated by RNA-binding proteins (RBPs), which regulate RNA processing and localisation. These RBPs have been implicated in neurodevelopment and specific types of neurodegeneration, including familial ALS in mouse models.

By conducting molecular experiments in cell lines, transgenic animals and human post-mortem tissue, the authors aimed to understand how differences in AS and APA correlate with development of human motor neurons and the impact of ALS-associated mutations on RNA processing.

They compared all messenger RNA (the molecules generated from DNA), called transcriptome, in human control cells and VCP mutant patient-derived stem cells. Of note, VCP mutants have been implicated in ALS.

Results evidenced increased IR as a dominant event during early differentiation of neurons. Importantly, the scientists observed that IR occurs prematurely in VCP mutants, compared to controls. The most relevant IR was found in the SFPQ mRNA across diverse ALS-causing mutations (VCP, SOD1 and FUS). SFPQ encodes a protein implicated in ALS-related pathways including RNA transcription, editing, and nerve fibers’ viability.

The data also showed that the SFPQ protein is less abundant in the nucleus of VCP mutants, and is absent in nuclei of motor neurons of mouse models and human sporadic ALS samples.

“Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS,” the authors wrote.