Oligodendrocyte Inclusion Pathology in Fragile X-Associated Tremor/Ataxia Syndrome
Yingratana McLennan1,2, Hassan Aliashrafzadeh1,2, Faith Zirkelbach-Ngai1,2
1Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis Health, Sacramento, California, USA.
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.
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