Biology subjects

Chiu, P.

Publications and source records attributed to Chiu, P..

3 recordsLinked to original sources

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↗

bioRxiv2026

Dopamine dynamics in human anterior cingulate cortex during Pavlovian-instrumental conflict

Dopamine is believed to modulate not only instrumental learning about the link between states, actions, and outcomes but also reflexive behaviours, such as a Pavlovian bias to approach in rewarding states and freeze in aversive ones. We studied these dual roles in the human brain, by combining intracranial dopamine recordings from the anterior cingulate cortex (ACC)-- a region implicated in behavioural and cognitive control -- with a motivational Go/NoGo task involving conflict between instrumental and Pavlovian action selection. We found evidence that dopamine in the ACC is involved in evaluating whether Pavlovian responding should guide behaviour. This computational motif was observed across multiple task events, including in response to rewards and punishments, and in analyses based on a reinforcement learning model. Our results indicate that dopamine supports learning at the more abstract level of behavioural policies in addition to the more concrete levels of states and actions.

neuroscience↗

bioRxiv2025

Human TDP-43 overexpression in zebrafish motor neurons triggers MND-like phenotypes through gain-of-function mechanism

Dysregulation of the TAR DNA-binding protein 43 (TDP-43), including intraneuronal cytoplasmic mislocalisation and aggregation is a feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), limbic-predominant age-related TDP-43 encephalopathy (LATE) and alzheimers disease (AD). Unravelling the causes and functional consequences of TDP-43 dysregulation is paramount to understanding disease mechanisms as well as identifying effective therapeutic targets. Here we present a comprehensive in vivo characterisation of three stable transgenic zebrafish models that express human TDP-43 variants in motor neurons. We demonstrate that overexpression of predominantly nuclear wildtype TDP-43, cytoplasm-targeted TDP-43, and an ALS-linked variant (G294V) each induce toxic gain-of-function effects, leading to impaired motor function, motor neuron loss, and muscle atrophy. Importantly, these models reveal distinct phenotypes, with the ALS-linked mutant exhibiting axonal transport deficits and neuromuscular junction disruption, while cytoplasmic mislocalised TDP-43 heightened susceptibility to oxidative stress. Two FDA-approved drugs used to treat ALS, edaravone and riluzole, were examined in these models and revealed that edaravone, but not riluzole, was effective in rescuing motor deficits associated with cytoplasmic TDP-43 expression and, to a lesser extent, mutant TDP-43G294V. Collectively, these findings reveal distinct pathological consequences of TDP-43 dysregulation, providing neuron-centric mechanistic insights, and establish the humanised TDP-43 zebrafish as an efficient system for preclinical therapeutic testing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/663393v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18c4a50org.highwire.dtl.DTLVardef@162df7forg.highwire.dtl.DTLVardef@3f2848org.highwire.dtl.DTLVardef@6d9439_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗