Neurotropic viruses and the TDP-43 axis: Reframing sporadic ALS through a viral-proteinopathy lens

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. While multiple genetic mutations such as Superoxide Dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP), Fused in Sarcoma (FUS), and chromosome 9 open reading frame 72 (C9orf72) account for a subset of familial cases, approximately 90% of ALS is sporadic and lacks clear genetic determinants. Pathological aggregation of transactive response TAR DNA-binding protein 43 (TDP-43) represents the unifying molecular hallmark in ~97% of all ALS cases, yet the upstream triggers of TDP-43 proteinopathy in sporadic ALS remain poorly understood. This review examines the hypothesis that neurotropic viruses act as triggers for TDP-43-mediated neurodegeneration. By analyzing the impact of enteroviruses, SARS-CoV-2, HIV-1, and human endogenous retrovirus-K (HERV-K), we review the mechanisms driving viral-induced proteostasis failure and subsequent motor neuron toxicity. Although establishing direct causation remains challenging, we propose that viral infections accelerate disease pathology in susceptible populations, highlighting the broader clinical need to mitigate viral risk factors in vulnerable neurological patients.