Publication highlights

Mislocalisation of the RNA binding protein TDP-43 is the pathological hallmark of the neurodegenerative conditions, motor neuron disease (MND) and frontotemporal dementia (FTD). This causes genes to be spliced differently, typically leading to loss of proteins or the formation of proteins with additional peptide sequences. This work uncovers another consequence of TDP-43 pathology: the formation of novel 3’UTRs (non-coding sequences towards the end of RNAs which regulate their functions). These were identified in stem cell-derived neurons and then found specifically in post mortem MND and FTD brains. Intriguingly, certain novel 3’UTRs can make RNAs more long-lived stop RNAs breaking down, leading to increased protein production. These findings shed light on potential novel molecular mechanisms of disease and offer new opportunities for identifying new disease biomarkers.

Abnormal movement of the RNA-binding protein TDP-43 from the nucleus to the cytoplasm in vulnerable brain cells is a hallmark of motor neuron disease. Losing the function of TDP-43 in the nucleus causes genetic sequences called ‘cryptic exons’ to be erroneously included in mature RNA transcripts. While these have been detected before, most of these events were predicted to produce faulty instructions that would be discarded. Whether or not these events translate into new proteins has remained an open question.

By removing TDP-43 in human stem cells grown in the lab, the researchers at the Crick, UCL and NIH discovered 65 new small proteins called ‘cryptic peptides’ which are produced when TDP-43 is lost from the nucleus. They detected 18 of these new proteins in cerebrospinal fluid samples from people with ALS or FTD. This discovery opens the door for both an exciting new fluid biomarker of disease progression in ALS/FTD and the intriguing possibility of cryptic peptides triggering an autoimmune response in disease.