Corticospinal propagation of full-length TDP-43 toxicity drives brain-to-muscle pathology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA metabolism, represent a pathological hallmark of all sporadic (sALS) and most familial (fALS) forms, underscoring its central role in disease pathophysiology. In affected neurons, full-length (FL) TDP-43 undergoes nuclear-to-cytoplasmic mislocalization, leading to aggregation and cellular dysfunction, and can be released to propagate pathology across neural and non-neural circuits. However, the in vivo toxicity and spreading capacity of FL TDP-43 remain poorly defined. Here, we show that purified, stable human FL TDP-43 was readily internalized by neuronal cells, where it induced aggregation and significantly reduced cell viability. In vivo, an acute unilateral stereotaxic infusion of FL TDP-43 into the rat primary motor cortex was sufficient to trigger a robust centrifugal propagation of pathology along the corticospinal axis and beyond the central nervous system (CNS). TDP-43 pathology spread from the motor cortex to the spinal cord and reached skeletal muscle. At the cellular level, propagated pathology was characterized by intraneuronal phosphorylated TDP-43 (pTDP-43) inclusions, accumulation of high-molecular-weight TDP-43 species, region-specific neurodegeneration, and pronounced mitochondrial vulnerability. Notably, skeletal muscle displayed impaired mitochondrial bioenergetics, accompanied by both motor and non-motor behavioral deficits. Collectively, our findings demonstrate neuron-to-neuron, brain-to-spinal cord and brain-to-muscle spreading of FL TDP-43 toxicity in vivo, establishing a mechanistic link between central TDP-43 pathology and peripheral dysfunction. This work identifies FL TDP-43 as an active driver of disease spreading in ALS and provides the basis for a non-transgenic, TDP-43-driven rat model of disease propagation.