Contemporary evidence for central nervous system mechanisms underlying chronic pain perception, modulation, and chronification in adults: a scoping review.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive and selective loss of upper and lower motor neurons. The disease typically manifests muscle weakness, spasticity, and atrophy, ultimately leading to paralysis and respiratory failure within a few years of symptom onset. Despite decades of research, treatment options remain extremely limited, and current therapies provide only modest effects on disease progression and patient survival. This urgent medical need highlights the importance of developing innovative therapeutic strategies that directly target the molecular mechanisms underlying ALS [,]. One of the most consistent pathological features of ALS is the mislocalization and aggregation of the transactive response DNA-binding protein 43 kDa (TDP-43). In the majority of ALS cases, TDP-43 loses its normal nuclear localization and accumulates in the cytoplasm, where it forms insoluble inclusions. This disruption contributes both to a loss of physiological nuclear functions and a gain of toxic cytoplasmic functions. Consequently, therapeutic strategies aiming to prevent or reverse TDP-43 pathology are of particular interest []. Antibody-based therapies have transformed treatment paradigms in several diseases. Single-chain variable fragments (scFvs) are antibody fragments composed of the variable region of heavy and light chains connected by a flexible linker. When expressed intracellularly, they function as intrabodies, directly binding to disease-related proteins such as TDP-43 within neurons [].