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Pathological features of FTLD-FUS in a Japanese population: analyses of nine cases
Zen Kobayashi1, Ito Kawakami, Tetsuaki Arai
1Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Neurology, JA Toride Medical Center, Toride, Ibaraki, Japan.
Abstract:
We investigated the pathological features of frontotemporal lobar degeneration (FTLD) with fused in sarcoma protein (FUS) accumulation (FTLD-FUS) in the Japanese population. Only one out of nine FTLD-FUS cases showed pathology that corresponds to atypical FTLD with ubiquitin-positive inclusions (aFTLD-U). Five were basophilic inclusion body disease (BIBD) and two were neuronal intermediate filament inclusion disease. The last case was unclassifiable and was associated with dystrophic neurites (DNs) as the predominant FUS pathology. The results of this study indicate an ethnic difference from western countries. In Japan, BIBD is the most common subtype of FTLD-FUS and aFTLD-U is rare, a finding which contrasts with aFTLD-U being the most common form in western countries. Immunohistochemical analyses of these FTLD-FUS cases reveal that FUS abnormally accumulated in neuronal cytoplasmic inclusions (NCIs) and DNs has an immunohistochemical profile distinct from that of normal, nuclear FUS. NCIs and DNs are more readily stained than the nuclei by antibodies to the middle portion of FUS. Antibodies to the carboxyl terminal portion, on the other hand, stain the nuclei more readily than NCIs and DNs. Such an immunohistochemical profile of NCIs and DNs was similar to that of cytoplasmic granular FUS staining which we previously reported to be associated with dendrites and synapses. Redistribution of FUS from the nucleus to the cytoplasm could be associated with the formation of abnormal FUS aggregates in FTLD-FUS.
Insights
In Japanese patients, basophilic inclusion body disease (BIBD) is the most common form of frontotemporal lobar degeneration with fused in sarcoma protein (FTLD-FUS), unlike in Western countries where atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) is more prevalent.
Area of Science:
- Neuropathology
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Frontotemporal lobar degeneration (FTLD) is a group of progressive neurodegenerative disorders.
- Fused in sarcoma protein (FUS) accumulation defines a specific subtype, FTLD-FUS.
- Understanding ethnic variations in FTLD-FUS pathology is crucial for diagnosis and research.
Purpose of the Study:
- To investigate the pathological features of FTLD-FUS in the Japanese population.
- To compare the prevalence of FTLD-FUS subtypes in Japan with Western cohorts.
- To characterize the immunohistochemical profile of abnormal FUS aggregates.
Main Methods:
- Analysis of nine Japanese FTLD-FUS cases.
- Histopathological classification of FTLD subtypes (aFTLD-U, BIBD, neuronal intermediate filament inclusion disease).
- Immunohistochemical staining for FUS protein in neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites (DNs).
Main Results:
- Basophilic inclusion body disease (BIBD) was the most common subtype (5/9 cases).
- Atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) was rare (1/9 cases), contrasting with Western populations.
- Abnormal FUS in NCIs and DNs showed distinct immunohistochemical staining patterns compared to nuclear FUS, suggesting cytoplasmic redistribution.
Conclusions:
- FTLD-FUS exhibits significant ethnic differences in subtype prevalence between Japan and Western countries.
- BIBD is the predominant FTLD-FUS subtype in Japan, while aFTLD-U is common in the West.
- The distinct immunohistochemical profile of cytoplasmic FUS aggregates may indicate altered protein processing and aggregation in FTLD-FUS pathogenesis.
