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

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.