TARDBP (TAR DNA Binding Protein)

In contrast, reduced PML-NBs in mature inclusions may reflect diminished cellular defense. These findings implicate PML-NBs in the pathogenesis of sporadic ALS.

In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.

Systemic PML delivery alleviates cognitive and motor deficits in mouse models of NIID and TDP-43 proteinopathy. These findings uncover a conserved spatial organization of nuclear inclusions and establish PML as a therapeutic effector for neurodegenerative diseases linked to protein aggregation.

P=N/A, N=5000, Recruiting, RWTH Aachen University

In conclusion, this study demonstrates the neuron-oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron-oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.

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.