Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology

Acta Neuropathologica Communications
H Jürgen WenzelRobert F Berman

Abstract

The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusi...Continue Reading

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Citations

Jul 15, 2020·International Journal of Molecular Sciences·Taejoon KimIm-Soon Lee
Mar 29, 2020·Frontiers in Molecular Biosciences·Saif N HaifyGian Gaetano Tartaglia
Feb 27, 2021·Curēus·Mitra KeshtkarjahromiSilvina Tonarelli

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Methods Mentioned

BETA
transgenic
PCR
electron microscopy
Fluorescence
laser capture microdissection
PCRs
electrophoresis
laser-capture microdissection

Software Mentioned

R
Leica Application Suite Advanced Fluorescence ( LAS AF )
TreadScan
Photoshop
Adobe Photoshop

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