Enteroviral Infection Leads To Transactive Response Dna-Binding Protein 43 Pathology in vivo.

(1) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons in the cerebral cortex, brainstems, and spinal cord, leading to progressive paralysis and eventual death. About 95% of all ALS cases are sporadic without known causes. Enteroviruses have been suspected to play a role in ALS due to their ability to target motor neurons and cause muscle weakness and paralysis. I vitro enteroviral infection results in cytoplasmic aggregation and cleavage of transactive response DNA binding protein-43 (TDP-43), a pathological hallmark of ALS. However, whether enteroviral infection can induce ALS-like pathologies in vivo remains to be characterized. In this study, neonatal BALB/C mice were intracranially inoculated with either a recombinant coxsackievirus B3 expressing enhanced GFP or mock-infected for 2, 5, 10, 30, and 90 days. Histological and imunohistochemical analysis of brain tissues demonstrated sustained inflammation (microglia and astrogliosis) and lesions in multiple regions of the brain (hippocampus, cerebral cortex, striatum, olfactory bulb, and putamen) in parallel with virus detection as early as two days for up to 90 days post-infection. Most notably, ALS-like pathologies, including cytoplasmic mislocalization of TDP-43, p62-, and ubiquitin-positive inclusions, were observed in the areas of infection. These data provide the first pathological evidence supporting a possible link between enteroviral infection and ALS.