TARDBP (TAR DNA Binding Protein)

At the post-transcriptional level in the nucleus, TDP-43 promotes Ref(2)P mRNA stability by interacting with the nuclear m6A reader protein Ythdc1, which facilitates recognition of N6-methyladenosine (m6A)-modified Ref(2)P transcripts and protects them from decay. Together, these findings delineate a dual regulatory mechanism by which TDP-43 controls Ref(2)P abundance and Yki proteostasis, providing new insights into the fine-tuning of Hippo pathway activity.

Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.

Importantly, we further identified the targets of TDP-43 in glial cells and decoded the differential RNA-binding protein (RBP) contexts of TDP-43-regulated aberrant splicing. These findings uncover that ALS and FTD patients have distinct dysfunctional cell populations harboring specific aberrant splicing signatures, suggesting varying cellular impacts and providing potential biomarkers and insights into molecular mechanisms underlying ALS/FTD.

Finally, we summarize the mechanisms by which TDP-43 facilitates the formation of ribonucleoprotein particles and this protein's involvement in mRNA localization and translation, as well as its associated molecular pathways. In conclusion, this review highlights the critical roles of TDP-43 and subsequent therapeutic strategies for treatment of neurodegenerative diseases and tumors.

Multichain simulations, which ensure the equality of the chemical potentials between the phases, show that the dense phase forms through nucleation and coarsening, resembling Ostwald ripening. The approaches developed here are broadly applicable and could help uncover assembly mechanisms in other intrinsically disordered proteins like TDP-43, which shares key features with FUS-LC.

Several dysregulated TEs overlapped regulatory regions near key AD-associated genes including DOC2A, ABCA7, PTK2B, IL34, ABCB9, PLD3, and TARDBP. These findings highlight cell-type-specific TE activation in AD and provide a foundation for investigating TE-mediated regulatory disruption and its therapeutic potential.

Deletion of ASC1 enhances a non-canonical form of autophagy that effectively counteracts TDP-43 induced autophagy inhibition despite reduced TOROID formation. Our findings highlight autophagy-not polysome sequestration-as a key mechanism underlying ASC1-mediated modulation of TDP-43 toxicity and suggest autophagy as a promising therapeutic target.

An antisense oligonucleotide targeting rs737540 significantly inhibited OSCC proliferation and reversed membrane cholesterol-induced resistance. This study provides novel insights into how genetic variants regulating alternative splicing contribute to OSCC risk and identifies potential therapeutic targets.

P=N/A, N=26, Completed, University of Pennsylvania | Active, not recruiting --> Completed

Furthermore, we review how emerging technologies like optogenetics and cryo-ET are decoding these mechanisms. Finally, we propose an integrated "See-and-Treat" theranostic paradigm, utilizing the unique material properties of condensates to design specific diagnostic probes and "molecular scalpels" for precision intervention.

In this review, we comprehensively explored the physiological and pathological roles of ANXA11 in neurodegeneration and other disorders, with a focus on LLPS, membrane dynamics, and amyloidogenesis. We discussed potential therapeutic strategies targeting the unique properties of ANXA11 and proposed several critical scientific questions that need to be explored.

Very early onset behavioral variant frontotemporal dementia (bvFTD) is an uncommon clinical presentation of frontotemporal dementia (FTD). A review of the literature identified 18 patients with an onset age of 25 years or younger, with the youngest patient reported to be 14 years old. Due to its early onset and primarily neuropsychiatric symptoms, bvFTD is often misdiagnosed as a psychiatric condition. In these cases, the most commonly reported pathology is tau protein, while mutations are frequently found in the MAPT gene. This differs from typical FTD, where the most commonly reported pathology is TDP-43 protein. Although rare, it is important to consider bvFTD even in very young patients presenting with new, significant behavioral disturbances.