Richter, G. | Search bioRxiv

bioRxiv2026

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

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), alzheimers 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. 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. 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/740184v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@12855eorg.highwire.dtl.DTLVardef@1f1e068org.highwire.dtl.DTLVardef@c3fb00org.highwire.dtl.DTLVardef@93f0ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

MondoA Drives Malignancy in cALL through Enhanced Adaptation to Metabolic Stress

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (cALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of cALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in cALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in cALL. Our findings give a novel insight into the function of MondoA in pediatric cALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored. Key PointsMondoA maintains aggressiveness and leukemic burden in common ALL, modulating metabolic stress response.

cancer biology↗