Oligodendrocyte Inclusion Pathology in Fragile X-Associated Tremor/Ataxia Syndrome

Abstract

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder marked by white matter degeneration and intranuclear inclusions. While astrocytic and neuronal inclusions are well-documented, oligodendrocytes were previously thought to lack such pathology. Objective: To demonstrate that oligodendrocytes in the prefrontal cortex of FXTAS patients do harbor intranuclear inclusions, with significantly higher burden in white matter than gray matter. Methods: Ubiquitin and p62 immunofluorescence and enzymatic staining were employed to confirm the presence of intranuclear inclusions in oligodendrocytes across multiple brain regions. Results: Oligodendrocytes contain inclusions and inclusion burden is correlated with FMR1 CGG repeat length (ρ = 0.97, P < 0.001) in white matter. Conclusions: These findings implicate oligodendrocyte dysfunction in FXTAS pathogenesis which may contribute to demyelination and white matter degeneration. Our data emphasize the need to consider cell type-specific mechanisms in FXTAS and support future therapeutic efforts aimed at restoring glial proteostasis. © 2025 International Parkinson and Movement Disorder Society.