COVID ‐19 Amplifies Sex‐Specific Dopamine and Glial Responses in a Parkinson's Disease Mouse Model

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Abstract
Background: Exposure to environmental agents, including viral infections, may increase Parkinson's disease (PD) susceptibility, especially in males, but the neurodegenerative risk extent of COVID‐19 remains uncertain. Objectives: We investigated the plausible link between severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and PD susceptibility across sexes. Methods: Mice overexpressing the human angiotensin‐converting enzyme 2 receptor (K18‐hACE2) were exposed to SARS‐CoV‐2 or 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) doses. This was followed by a two‐hit experiment in which mice received a moderate MPTP dose and SARS‐CoV‐2 11 days post‐MPTP. Striatal viral titer was measured 4 days postinfection (dpi). After 14 dpi, striatal dopamine and its metabolites (3,4‐dihydroxyphenylacetic acid, 3‐methoxytyramine, homovanillic acid), nigrostriatal degeneration, and glial responses in males and females were compared. Results: Only in males, SARS‐CoV‐2 resulted in progressive dopamine metabolic dysregulation by day 21. Coexposed females showed less weight loss than males. Coexposed males showed significant nigrostriatal degeneration, together with robust nigral astrocytic and microglial reactivity exceeding individual effects. In females, MPTP and/or SARS‐CoV‐2 had minimal effects on dopamine and its metabolism, degeneration, and microglial reactivity, whereas coexposure was associated with significant nigral astrocytic reactivity. In coexposed males, striatal microglia showed enhanced territorial spacing, whereas in females, they became more clustered, possibly because of an enrichment of cells with larger soma and retracted processes. In males, single or dual exposure stressed degenerating dopamine neurons to shrink and dilate their Golgi bodies, more prominently in the coexposed group. Conclusions: This study reports the sex‐dependent COVID‐19 effects on mice prodromal PD with a differential glial contribution, supporting glial‐ and sex‐based medical approaches. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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