SFPQ dysregulation promotes TDP-43 pathology through a pathogenic feedback loop

<jats:title>Abstract</jats:title> <jats:p>TDP-43 proteinopathies comprise a group of clinically distinct neurodegenerative disorders unified by common pathological changes in the RNA-binding protein TDP-43, including nuclear loss of function (LOF), cytoplasmic mislocalisation and aggregation. The presence of these hallmarks across diverse diseases, such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), alzheimer’s disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), suggests the involvement of convergent upstream regulatory mechanisms. This study identified SFPQ (Splicing Factor Proline and Glutamine Rich) as one such factor.</jats:p> <jats:p>The depletion of nuclear SFPQ, in addition to its cytoplasmic accumulation and aggregation has been described across ALS, AD and FTD patient studies and in multiple genetic models of these diseases. Evidence to date places SFPQ pathology downstream of TDP-43 dysfunction. This study provided further evidence that TDP-43 drives SFPQ pathology while revealing a reciprocal role for SFPQ in regulating TDP-43 homeostasis. Our data shoed that SFPQ LOF was associated with a shift in TDP-43 RNA isoform usage away from the canonical protein-coding transcript towards isoforms predicted to undergo nonsense-mediated decay (NMD). Consistent with this, TDP-43 protein expression was reduced across multiple model systems in which SFPQ expression was suppressed. Furthermore, cytoplasmic accumulation of SFPQ was found to promote the mislocalisation of TDP-43 and its sequestration within SFPQ-containing cytoplasmic condensates that exhibited progressively reduced molecular mobility over time.</jats:p> <jats:p>Collectively, these findings identify SFPQ as an active contributor to multiple facets of TDP-43 pathology, support a bidirectional relationship between the two proteins, and suggest the existence of a feed-forward, self-amplifying mechanism that may contribute to disease progression in TDP-43 proteinopathies.</jats:p> <jats:sec> <jats:title>Graphical Abstract</jats:title> <jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="740184v1_ufig1" position="float" orientation="portrait"/> </jats:fig> </jats:sec>