2025 年 42 巻 2 号 p. 90-95
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of motor neurons. A prominent pathological hallmark of ALS is the aggregation of TAR DNA–binding protein 43 (TDP–43), an RNA/DNA–binding protein involved in various cellular processes, including RNA metabolism and stress granule dynamics. In sporadic ALS, cytoplasmic aggregation of TDP–43 and its depletion in the nucleus are widely recognized as pathological features. Although the precise mechanisms underlying TDP–43 pathology remain unclear, both gain–of–function and loss–of–function effects are believed to contribute to disease progression.
Recent research efforts have focused on developing therapeutic strategies targeting TDP–43 abnormalities. Among these, bosutinib, a Src/c–Abl inhibitor, and antisense oligonucleotides targeting ATXN2 have been identified as potential therapeutic agents, with clinical trials have been conducted. Furthermore, immunotherapy, including monoclonal antibodies (mAbs) and single–chain variable fragments (scFvs), has shown significant promise. These antibodies selectively bind to pathological TDP–43 aggregates, facilitating their clearance via proteasome– and autophagy–mediated pathways while sparing physiological TDP–43. Notable examples include VH7Vk9 scFv and 3B12A scFv, which have demonstrated preclinical efficacy in reducing TDP–43 aggregation, mitigating neuroinflammation, and improving motor and cognitive functions.
These therapeutic approaches aim to modulate TDP–43 dynamics, prevent its misfolding, and restore cellular proteostasis. However, the clinical translation of TDP–43–targeted therapies presents significant challenges, particularly in ensuring the safety and specificity of these interventions. The development of efficient delivery systems, such as viral vectors, is critical for their therapeutic success. Future research should focus on optimizing these strategies and evaluating their long–term effects in ALS and other TDP–43 proteinopathies.
This manuscript provides an overview of TDP–43 pathology and highlights recent advancements in molecular and antibody–based therapeutic interventions, offering insights into potential treatment avenues for ALS.
