FUS-Immunoreactive Intranuclear Inclusions in Neurodegenerative Disease
Article first published online: 21 SEP 2009
© 2009 The Authors; Journal Compilation © 2009 International Society of Neuropathology
Volume 20, Issue 3, pages 589–597, May 2010
How to Cite
Woulfe, J., Gray, D. A. and Mackenzie, I. R.A. (2010), FUS-Immunoreactive Intranuclear Inclusions in Neurodegenerative Disease. Brain Pathology, 20: 589–597. doi: 10.1111/j.1750-3639.2009.00337.x
- Issue published online: 12 APR 2010
- Article first published online: 21 SEP 2009
- Received 11 August 2009; accepted 5 September 2009.
- CNS tumors;
- diagnostic and prognostic markers;
Neuronal intranuclear inclusions (NIIs) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by NIIs in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, “fused-in-sarcoma” (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD-IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD-UPS, formerly known as atypical FTLD-U), both of which are characterized by the presence of NII. The objective of the present study was to determine the range of neurodegenerative disorders characterized by FUS-positive NIIs. Immunostaining for FUS revealed intense reactivity of NIIs in FTLD-IF and FTLD-UPS as well as in Huntington's disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of NIIs in inherited forms of FTLD-TDP caused by GRN and VCP mutations, fragile-X-associated tremor ataxia syndrome, or oculopharyngeal muscular dystrophy. In a cell culture model of Huntington's disease, NIIs were intensely FUS-positive. NII-bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by NIIs may interfere with its normal nuclear localization.