Brain Advance Access originally published online on October 24, 2005
Brain 2006 129(1):256-271; doi:10.1093/brain/awh650
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Protein composition of the intranuclear inclusions of FXTAS
1 Department of Biochemistry and Molecular Medicine, 2 Department of Pathology and 3 M.I.N.D. Institute, School of Medicine and 4 Department of Chemistry, University of California, Davis, CA, USA
Correspondence to: Paul J. Hagerman, MD, PhD, Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA, USA E-mail: pjhagerman{at}ucdavis.edu
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55–200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS.
Key Words: dementia; neurodegeneration; Parkinson; RNA toxicity; trinucleotide repeat; lamin
Abbreviations: FMR1 = fragile X mental retardation 1 gene; FMRP = FMR1 protein; FT-ICR = Fourier transform ion cyclotron resonance; FXTAS = fragile X-associated tremor/ataxia syndrome; hnRNP A2 = heterogeneous nuclear ribonucleoprotein A2; HSP = heat shock protein; LC = liquid chromatography; MBNL1 = muscle blind-like protein 1; MBP = myelin basic protein; MS = mass spectrometry; XCorr = minimum cross-correlation value
Received April 20, 2005. Revised July 27, 2005. Accepted September 3, 2005.
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