FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease

Mori, Fumiaki; Tanji, Kunikazu; Kon, Tomoya; Odagiri, S; Hattori, Manabu; Hoshikawa, Yasuko; Kono, Chikao; Yasui, Kohichiroh; Yokoi, Sana; Hasegawa, Yasuhiro; Yoshida, Mari; Wakabayashi, Keiji

doi:10.1111/j.1365-2990.2011.01217.x

Cited by 26 publications

(28 citation statements)

References 26 publications

(57 reference statements)

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“…However, it must be mentioned that INIBD has been reported in elderly individuals without clinical symptoms, including a case reported in a community‐based study . Immunoreactivity for FUS has been reported for the intranuclear inclusions and also for optineurin . Interestingly, in neurons with small inclusions, or inclusions where only the rim was FUS immunoreactive, the normal nuclear staining for FUS remained.…”

Section: Discussionmentioning

confidence: 99%

“…It is characterized by eosinophilic nuclear inclusions that are immunoreactive for ubiquitin and related proteins in neuronal but also in glial cells . Interestingly, these inclusions can be immunolabelled with antibodies against FUS, which is a major component of inclusions in a familial form of amyotrophic lateral sclerosis, and are found in atypical frontotemporal lobar degeneration with ubiquitinated inclusions, basophilic inclusion body disease and intermediate neurofilament inclusion body disease . Contrasting with INIBD, tauopathies are more frequent and are classified by the presence and morphology of tau immunoreactive neuronal or glial inclusions.…”

Section: Introductionmentioning

confidence: 99%

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Atypical sporadic CJD‐MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease

Berghoff

Trummert²,

Unterberger

et al. 2015

Neuropathology

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We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Atypical sporadic CJD‐MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease

Berghoff

Trummert²,

Unterberger

et al. 2015

Neuropathology

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“…A comparative analysis of six cases of ALS‐ FUS revealed glial inclusions; however, in spite of a ramified morphology of some of these, an astrocytic origin could not be confirmed by double‐labeling experiments using sensitive and specific markers of these cell types, therefore, these inclusions were not considered to be astroglial . Finally, the glial intranuclear inclusions in intranuclear inclusion body disease show FUS immunoreactivity .…”

Section: Pag In Non‐tauopathy Neurodegenerative Diseasesmentioning

confidence: 95%

Protein astrogliopathies in human neurodegenerative diseases and aging

2017

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Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-β, prion protein, tau, α-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP-43) is not unprecedented or unusual in neurodegenerative diseases. Morphological characterization of PAG is considered, however, only for the neuropathological diagnosis and classification of tauopathies. Astrocytic tau pathology is seen in primary frontotemporal lobar degeneration (FTLD) associated with tau pathologies (FTLD-Tau), but also in the form of aging-related tau astrogliopathy (ARTAG). Importantly, ARTAG shares common features with primary FTLD-Tau as well as with the astroglial tau pathologies that are thought to be hallmarks of a brain injury related tauopathy known as chronic traumatic encephalopathy (CTE). Supported by experimental observations, the morphological variability of PAG might reflect distinct pathogenic involvement of different astrocytic populations. PAG might indicate astrocytic contribution to spreading or clearance of disease-associated proteins, however, this might lead to astrocytic dysfunction and eventually contribute to the degeneration of neurons. Here we review recent advances in understanding ARTAG and other related forms of PAG.

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“…Although the major component of intranuclear inclusions in this disease is uncertain, they are immunoreactive for FUS [9]. Mutations in the gene encoding the FUS protein are now known to be the cause of familial ALS [6].…”

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confidence: 98%

Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease

et al. 2012

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Ubiquilin-1 (UBQLN1), a member of the ubiquitin-like protein family (UBQLN1-4), is associated with neurofibrillary tangles in Alzheimer's disease (AD) and with Lewy bodies (LBs) in Parkinson's disease (PD) [7]. Mutations in UBQLN2 cause dominant X-linked amyotrophic lateral sclerosis (ALS) [4]. UBQLN2-immunoreactive neuronal cytoplasmic inclusions (NCIs) are found in the hippocampus and spinal cord in ALS with or without UBQLN2 mutation. Moreover, a distinct pattern of UBQLN2 pathology is seen in cases of ALS and frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) showing C9ORF72-hexanucleotide repeat expansion [2], which is the most common genetic abnormality in ALS/ FTLD [3,12]. Here we report that UBQLN2 immunoreactivity is present in cytoplasmic and nuclear inclusions in various neurodegenerative diseases.Post-mortem cases of sporadic ALS (n = 5), FTLD-TDP type B (n = 4), PD (n = 5), neocortical-type DLB (n = 5), multiple system atrophy (MSA; n = 5), AD (n = 5), Pick's disease (n = 4), progressive supranuclear palsy (n = 4), corticobasal degeneration (n = 4), argyrophilic grain disease (n = 4), Huntington's disease (HD; n = 3), dentatorubral-pallidoluysian atrophy (DRPLA; n = 5), spinal and bulbar muscular atrophy (SBMA; n = 3), spinocerebellar ataxia type 1 (SCA1; n = 3), SCA2 (n = 1), SCA3 (n = 5), intranuclear inclusion body disease (INIBD; n = 5) and controls (n = 5) were utilized. Immunohistochemistry was performed as described previously [10] with the following antibodies: UBQLN2, UBQLN1, phosphorylated a-synuclein, phosphorylated tau, ubiquitin, polyglutamine and TDP-43 (Online Resource). The total number of inclusions immunostained with each antibody was counted in contiguous sections.In controls, neuronal nuclei were weakly immunolabeled with anti-UBQLN2 (Fig. 1a). UBQLN2-immunoreactive NCIs were found in the temporal cortex in FTLD-TDP (25 % relative to TDP-43-positive inclusions) as well as in the spinal cord in ALS (14 %) (Fig. 1b). In PD/DLB, both brainstem type and cortical LBs were intensely stained (Fig. 1c, d). Contiguous sections stained with anti-UB-QLN2 and anti-a-synuclein revealed that 21 % of brainstem-type LBs and 48 % of cortical LBs were positive for UBQLN2. In MSA, 82 % of glial cytoplasmic inclusions (GCIs) were positive for UBQLN2 (Fig. 1e). In HD, DRPLA, SBMA, SCA1-3 and INIBD, more than 95 % of neuronal nuclear inclusions (NNIs) were strongly immunolabeled ( Fig. 1f-l). In addition, Marinesco bodies (MBs)

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FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease

Abstract: These findings suggest that FUS is incorporated into INIBs in both neurones and glial cells and that loss of normal FUS immunoreactivity may result from reduced protein expression and/or sequestration within inclusions.

Cited by 26 publications

References 26 publications

Atypical sporadic CJD‐MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease

Atypical sporadic CJD‐MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease

Protein astrogliopathies in human neurodegenerative diseases and aging

Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusion body disease

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