Preventing the misfolding or aggregation of TDP-43 is the most actively pursued disease-modifying strategy to treat amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In our work, we provide proof of concept that native state stabilization of TDP-43 is a viable and effective strategy for treating TDP-43 proteinopathies. In Chapter 2 of this thesis, we provide proof of concept that native state stabilization of monomeric TDP-43 is a viable and more effective therapeutic strategy for treating TDP-43 proteinopathies. Firstly, we used published Cryo-EM structures of TDP-43 fibrils to design C-terminal amino acid substitutions, which mimic native posttranslational modifications, to disrupt TDP-43 aggregation. Secondly, we showed that these mutations (S333D/S342D) stabilize monomeric TDP-43 for days without altering its physiological and cellular properties (subcellular localization). Thirdly, we demonstrated that binding native oligonucleotide ligands stabilizes monomeric TDP-43 and prevents its fibrillization and phase separation in the absence of direct binding with the aggregation-prone C-terminal domain. Fourthly, we showed that the monomeric TDP-43 variant (TDP-43S333D/S342D) could be induced to misfold and aggregate in a controlled manner, thus enabling the design and implementation of the first high-throughput screening assay to identify native state stabilizers of TDP-43. In Chapter 3 of this thesis, taking advantage of the previously reported aggregation-inducible and monomeric TDP-43 variant, we scaled up our screen to identify chemical stabilizers of TDP-43 that capture its functional species. Another 8 hit compounds that showed an apparent inhibitory effect on the size increase of TDP-43 during its aggregation were identified in the DLS-based assay. Our data showed that these compounds can bind to both the variant and wild-type TDP-43 with affinities from low to moderate micromolar range. In addition, all compounds were shown to inhibit the aggregation of full-length TDP-43 in a dose-dependent manner, with some of these compounds also inhibiting the aggregation of its amyloid core peptide 279-360. Electron microscopy analysis indicated that these compounds actually stabilized TDP-43 in its various oligomeric states. Subsequent mass photometry analysis of the protein-ligand complexes revealed that some compounds may maintain TDP-43 as stable monomers. This study serves as a strong support for targeting TDP-43 aggregation using native-state stabilizers to rescue its proteinopathies. In Chapter 4 of this thesis, we developed a new protocol to generate different stable forms of unmodified and small-molecule-induced TDP-43 oligomers and investigated their ability to 1) retain some of the functional properties of TDP-43; 2) seed the aggregation of TDP-43; and 3) exert toxic effects upon addition to neurons. We showed that coincubation of TDP-43 with small molecules, such as epigallocatechin gallate (EGCG), dopamine, and 4-hydroxynonenal (4-HNE), increased the production yield of TDP-43 stable oligomers, which could be further purified by size-exclusion chromatography. Interestingly, despite significant differences in the morphology and size distribution of the different TDP-43 oligomer preparations, they all retained the ability to bind to nucleotide RNA. Surprisingly, none of these oligomer preparations could seed the aggregation of TDP-43 core peptide 279-360. Finally, we showed that all 4 types of TDP-43 oligomers exert very mild cytotoxicity to primary neurons. Our results suggest that functional TDP-43 oligomers, other than the native states, could also be stabilized by chemical modulators and might serve as a new approach to halt TDP-43 aggregation in different NDDs.