22/11/22
Richard Taylor and colleagues have identified a new hallmark of motor degeneration characterised by fragments of aberrant mRNA accumulating in axons, offering fresh insights into neurodegeneration.
With our ageing population, neurodegeneration and neurodegenerative disorders are becoming increasingly pressing to solve. Despite the increasing prevalence of these disorders, the mechanisms and biological processes underlying these disorders are not well understood and many precursors to the onset of symptoms are unidentified. SFPQ misregulation has been known to be hallmark of amyotrophic lateral sclerosis (ALS) for some time but it has been unclear how such misregulation might contribute to degeneration.
In exciting new work, Richard Taylor, other members of the Houart lab and CDN colleagues Fursham Hamid and Euguene Makeyev have identified a previously unknown feature found in ALS. In their work, published in Nature Communications, Taylor et al. explore the impact of losing SFPQ in a zebrafish model. The authors found that indeed loss of SFPQ does lead to degeneration but that prior to the onset of this, neurons lacking the protein show axon extension, branching and synaptogenesis defects. Subcellular transcriptomic analysis showed that loss of neuronal SFPQ produces a complex set of intron-retaining (IR) transcripts which code for neuron-specific proteins that accumulate in neurites. Some of the local IR mRNAs are prematurely terminated within the retained intron (PreT-IR). Through further experiments, Taylor et al. showed that PreT-IR mRNAs undergo intronic polyadenylation, nuclear export, and are targeted to neurites.
Taylor and colleagues then sought to understand the medical relevance of their findings and found the same IR and PreT-IR mRNAs were enriched in RNAseq datasets derived from tissue from patients with both familial and sporadic ALS.
These new findings not only challenge the dogma that prematurely terminated mRNAs are targeted for degradation but offer novel insights into the mechanisms underlying ALS and possibly other neurodegenerative conditions. The findings offer the potential for a new avenue of therapy in ALS patients, restoring SFPQ function in neurons to prevent their degeneration.
