SARS-CoV-2 Infection Induces Dopaminergic Neuronal Loss in Midbrain Organoids

COVID-19 is mainly associated with respiratory symptoms, although several reports show that SARS-CoV-2 affects the nervous system. We evaluated the effects of SARS-CoV-2 infection on human derived midbrain organoids by exposing them to the virus (multiplicity of infection 0.05, 16-h exposure) and analyzing cellular and molecular changes at 4 and 28 days post-infection using immunofluorescence microscopy and RNA sequencing. SARS-CoV-2 nucleocapsid protein preferentially colocalized with tyrosine hydroxylase-positive (TH+) dopaminergic neurons, inducing neurite fragmentation and cellular stress. Transcriptomic analysis revealed dysregulation of pathways related to cell stress and death, DNA damage response, neurodevelopment, and neuronal survival at both timepoints. Persistent alterations in vesicle trafficking, Notch signaling, and mitochondrial function were observed at 28 days post-infection. Analysis of non-coding RNA expression highlighted dysregulated genomic regions associated with viral replication and neurite growth. These findings demonstrate selective vulnerability of dopaminergic neurons to SARS-CoV-2 infection with persistent molecular alterations, providing mechanistic insights into potential neurological consequences of COVID-19.