期刊
JOURNAL OF MOLECULAR NEUROSCIENCE
卷 45, 期 3, 页码 409-421出版社
HUMANA PRESS INC
DOI: 10.1007/s12031-011-9549-8
关键词
Neuronal intermediate filament inclusion disease; Frontotemporal lobar degeneration; FUS; Neurofilament; alpha-Internexin; Immunoelectron microscopy
资金
- Jean Shanks Foundation
- Wellcome Trust, UK [GR066166AIA]
- National Institute on Aging of the National Institutes of Health [P50 AG05681, P01 AG03991]
- Friedman Award
Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of alpha-internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the loosely aggregated cytoplasmic inclusions, 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer compact cytoplasmic inclusions and tangled twine ball inclusions were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations.
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