Fragile X mental retardation protein expression in Alzheimer's disease.

The FMR1 protein product, FMRP, is an mRNA binding protein associated with translational inhibition of target transcripts. One FMRP target is the amyloid precursor protein (APP) mRNA, and APP levels are elevated in Fmr1 KO mice. Given that elevated APP protein expression can elicit Alzheimer's disease (AD) in patients and model systems, we evaluated whether FMRP expression might be altered in Alzheimer's autopsy brain samples and mouse models compared to controls.

CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG.

Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice.

Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5' untranslated region (UTR) of the FMR1 gene. Premutation-sized repeats increase FMR1 transcription but impair rapid translation of the Fragile X mental retardation protein (FMRP), which is absent in Fragile X Syndrome (FXS). Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR)-mediated synaptic translation, allowing for dendritic synthesis of several proteins.

Neurodegeneration the RNA way.

The expression, processing, transport and activities of both coding and non-coding RNAs play critical roles in normal neuronal function and differentiation. Over the past decade, these same pathways have come under scrutiny as potential contributors to neurodegenerative disease. Here we focus broadly on the roles of RNA and RNA processing in neurodegeneration.