tdp 43

EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. EN6 is a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal the vacuolar H+ ATPase (v-ATPase).

G923-0271 is a TDP-43 inhibitor that improves disease phenotypes in TDP-43 nematode models and reduces the overexpression of human TDP-43 at the cellular level, making it useful for studying diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

UP163 enhances ATPase activity and activates valosin-containing protein (VCP), with an EC50 of 9.0 μM. It also reduces MG-132-induced TDP-43 aggregation.

Glutathione monoethyl ester, a derivative of glutathione, can protect motor neuron cells (NSC-34) from TDP-43 pathology caused by mutations, which includes reducing aggregate formation, nuclear clearance, reactive oxygen species (ROS) production, and cell death.

AIM4 is a compound known for inhibiting TDP-43 aggregation. It demonstrates good biocompatibility and anti-inflammatory activity, making it a valuable agent in research for diseases such as amyotrophic lateral sclerosis (ALS).

TTBK1-IN-2 (N-[4-(4-chlorophenoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine) is an inhibitor of Tau-Tubulin kinase (TTBK1) with IC50s of 0.24 and 4.22 µM. TTBK1-IN-2 reduces TDP-43 phosphorylation both in cell cultures and the spinal cord of transgenic TDP-43 mice.

rTRD01 is a TDP-43 ligand that selectively binds to the RRM1 and RRM2 domains of TDP-43, exhibiting a dissociation constant (Kd) of 89 µM for TDP-43 102–269. The compound can partially disrupt the interaction between TDP-43 and the hexanucleotide RNA repeat associated with the c9orf72 gene, implicated in certain neurodegenerative diseases. rTRD01 holds potential for use in neurodegenerative disease research [1].