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Brain Advance Access published online on October 24, 2005
Brain, doi:10.1093/brain/awh650
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received April 20, 2005
Revised July 27, 2005
Accepted September 3, 2005

Article

Protein composition of the intranuclear inclusions of FXTAS

C. K. Iwahashi 1, D. H. Yasui 1, H.-J. An 2, C. M. Greco 3, F. Tassone 1, K. Nannen 1, B. Babineau 1, C. B. Lebrilla 2, R. J. Hagerman 4, and P. J. Hagerman 1*

1 Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA
2 Department of Chemistry, University of California, Davis, CA, USA
3 Department of Pathology, University of California, Davis, CA, USA
4 M.I.N.D. Institute, School of Medicine, University of California, Davis, CA, USA

* To whom correspondence should be addressed.
P. J. Hagerman, E-mail: pjhagerman{at}ucdavis.edu


  Abstract

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.

Keywords: dementia; neurodegeneration; Parkinson; RNA toxicity; trinucleotide repeat; lamin.
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