Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis
Na-Young Park, Yunseok Heo, Ji Won Yang, Je Min Yoo, Hye Ji Jang, Ju Hee Jo, Su Jeong Park, Yuxi Lin, Joonhyeok Choi, Hyeonjin Jeon, Sun Hyung Joo, Gaeun Bae, Donghoon Kim, Ju-Hee Kim, Wade F. Zeno, Jong Bo Park, Noriyoshi Isozumi, Tomohide Saio, Seung Hyun Kim, Ho-Jae Lee, Byung Hee Hong, Minyeop Nahm, Young‐Ho Lee, Young Bin Hong
Abstract
Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.