Fused In Sarcoma Pathology Research Articles

Changing perspectives on frontotemporal dementia: A review.

This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP-43 or more rarely fused-in-sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP-43 pathology, and speech or limb apraxia tau pathology. The co-occurrence of MND predicts TDP-43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non-fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub-variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies.

FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy

As is the case with neurodegenerative diseases, abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke. However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis. FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke.

A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient’s brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression.

FUS regulates autophagy by mediating the transcription of genes critical to the autophagosome formation.

Fused in sarcoma (FUS) is a ubiquitously expressed RNA/DNA-binding protein that plays different roles in the cell. FUS pathology has been reported in neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in FUS have also been linked to a subset of familial ALS. FUS is mainly localized in the nucleus although it shuttles between the nucleus and the cytoplasm. ALS-linked mutations cause the accumulation of the FUS protein in cytoplasm where it forms stress granule-like inclusions. The protein- and RNA-containing inclusions are reported to be positive of autophagosome markers and degraded by the autophagy pathway. However, the role of FUS in the autophagy pathway remains to be better understood. Using immunoblot and confocal imaging techniques in this study, we found that FUS knockout (KO) cells showed a decreased basal autophagy level. Rapamycin and bafilomycin A1 treatment showed that FUS KO cells were not able to initiate autophagy as efficiently as wild-type cells, suggesting that the autophagosome formation is affected in the absence of FUS. Moreover, using immunoblot and quantitative PCR techniques, we found that the mRNA and protein levels of the genes critical in the initial steps of the autophagy pathway (FIP200, ATG16L1 and ATG12) were significantly lower in FUS KO cells. Re-expressing FUS in the KO cells restored the expression of FIP200 and ATG16L1. Our findings demonstrate a novel role of FUS in the autophagy pathway, that is, regulating the transcription of genes involved in early stages of autophagy such as the initiation and elongation of autophagosomes.

Young-onset frontotemporal dementia with FUS pathology

Frontotemporal dementia (FTD) is an uncommon cause of behavioural change in adults under the age of 50. A 44-year-old man presented with progressive neuropsychiatric disturbance characterised by social withdrawal, apathy,...

N‐terminal phosphorylation of Fused in Sarcoma (FUS) protein results in distinct changes to the cellular proteome that differ from the P525L model of pathology

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share many genetic and neuropathological markers of diseases (http://doi.org/10.1016/j.neuron.2013.07.033). One such neuropathological marker is the abnormal cytoplasmic aggregation of the Fused in Sarcoma (FUS) protein. FUS is a RNA/DNA binding protein involved in gene transcription, mRNA splicing, DNA‐repair pathways, and mRNA transport. To accomplish its many roles in the cell, FUS shuttles between the nucleus and cytoplasm carrying mRNA transcripts to distinct cellular locations. However, in FTD and ALS with FUS pathology, nuclear/cytoplasmic shuttling of FUS is disrupted resulting in its mislocalization into insoluble cytoplasmic inclusions (http://doi.org/10.1080/15476286.2016.1211225). Most pathological genetic mutations (including P525L) do not cause FTD (http://doi.org/10.1038/nn.3584). Therefore, non‐genetic factors such as post‐translational modifications may trigger FTD‐FUS pathology. Our lab discovered that double‐strand DNA damage induces phosphorylation of FUS (p‐FUS) at multiple N‐terminal sites leading to an accumulation of p‐FUS in the cytoplasm, yet the consequence of this cytoplasmic p‐FUS remain unknown (http://doi.org/10.1523/JNEUROSCI.0172‐14.2014). We set out to use an unbiased proximity labeling approach termed APEX2 to interrogate the WT FUS, P525L FUS, and p‐FUS proteomes.MethodWe and others have mapped the major N‐terminal phosphorylation sites, enabling the creation of a phosphomimetic variant of FUS (PM FUS) that mimics the phosphorylation of FUS caused by double‐stranded DNA damage. We then fused WT FUS, PM FUS, or P525L FUS to the engineered peroxidase, APEX2, and used proximity‐dependent biotin tagging to enrich for all proteins near the APEX2 complex. Biotin‐tagged proteins were identified and quantified using label‐free quantitative proteomics. Intensity readings were then corrected against controls using SAINT (Significance Analysis of INTeractome), a series of software tools that assign confidence values to observed protein‐protein interactions (http://doi.org/10.1038/nmeth.1541).ResultWe identified 3,313 differentially expressed proteins that were enriched in PM FUS, P525L FUS, and/or WT FUS over background. As expected, PM FUS enriched for cytoplasmic proteins as compared to WT FUS. Interestingly, the protein interactomes for PM FUS and P525L FUS separated independently of each other, suggesting distinct pathological mechanisms.ConclusionFindings from these studies will inform whether phosphorylation is a mechanism that could be targeted to shift FUS localization in FTD with FUS pathology.

Divergent FUS phosphorylation in primate and mouse cells following double-strand DNA damage

Fused in sarcoma (FUS) is a RNA/DNA protein involved in multiple nuclear and cytoplasmic functions including transcription, splicing, mRNA trafficking, and stress granule formation. To accomplish these many functions, FUS must shuttle between cellular compartments in a highly regulated manner. When shuttling is disrupted, FUS abnormally accumulates into cytoplasmic inclusions that can be toxic. Disrupted shuttling of FUS into the nucleus is a hallmark of ~10% of frontotemporal lobar degeneration (FTLD) cases, the neuropathology that underlies frontotemporal dementia (FTD). Multiple pathways are known to disrupt nuclear/cytoplasmic shuttling of FUS. In earlier work, we discovered that double-strand DNA breaks (DSBs) trigger DNA-dependent protein kinase (DNA-PK) to phosphorylate FUS (p-FUS) at N-terminal residues leading to the cytoplasmic accumulation of FUS. Therefore, DNA damage may contribute to the development of FTLD pathology with FUS inclusions. In the present study, we examined how DSBs effect FUS phosphorylation in various primate and mouse cellular models. All cell lines derived from human and non-human primates exhibit N-terminal FUS phosphorylation following calicheamicin γ1 (CLM) induced DSBs. In contrast, we were unable to detect FUS phosphorylation in mouse-derived primary neurons or immortalized cell lines regardless of CLM treatment, duration, or concentration. Despite DNA damage induced by CLM treatment, we find that mouse cells do not phosphorylate FUS, likely due to reduced levels and activity of DNA-PK compared to human cells. Taken together, our work reveals that mouse-derived cellular models regulate FUS in an anomalous manner compared to primate cells. This raises the possibility that mouse models may not fully recapitulate the pathogenic cascades that lead to FTLD with FUS pathology.

Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis.

Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. In this study, we applied a novel detection method using a conventional antigen retrieval technique with Sudan Black B treatment to identify FUS-positive inclusions in sALS patients. We classified pathological motor neurons into 5 different categories according to the different aggregation characteristics of FUS and TDP-43. Although the granular type was more dominant for inclusions with TDP-43, the skein-like type was more often observed in FUS-positive inclusions, suggesting that these 2 proteins undergo independent aggregation processes. Moreover, neurons harboring FUS-positive inclusions demonstrated substantially reduced expression levels of dynactin-1, a retrograde motor protein, indicating that perturbation of nucleocytoplasmic transport is associated with the formation of cytoplasmic inclusions of FUS in sALS.

The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization.

The RBP associated with lethal yellow mutation (RALY) is a member of the heterogeneous nuclear ribonucleoprotein family whose transcriptome and interactome have been recently characterized. RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression. PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. Confirming that inhibiting FUS methylation increases its nuclear import, we report that RALY knockout enhances FUS NLS mutants’ nuclear translocation, hence decreasing aggregate formation. Furthermore, we characterize the RNA-dependent interaction of RALY with FUS in motor neurons. We show that mutations in FUS NLS as well as in RALY NLS reciprocally alter their localization and interaction with target mRNAs. These data indicate that RALY’s activity is impaired in FUS pathology models, raising the possibility that RALY might modulate disease onset and/or progression.

Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function

The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an exvivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology.

HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls. Patient-derived MNs show typical cytoplasmic FUS pathology, hypoexcitability, as well as progressive axonal transport defects. Axonal transport defects are rescued by CRISPR/Cas9-mediated genetic correction of the FUS mutation in patient-derived iPSCs. Moreover, these defects are reproduced by expressing mutant FUS in human embryonic stem cells (hESCs), whereas knockdown of endogenous FUS has no effect, confirming that these pathological changes are mutant FUS dependent. Pharmacological inhibition as well as genetic silencing of histone deacetylase 6 (HDAC6) increase α-tubulin acetylation, endoplasmic reticulum (ER)–mitochondrial overlay, and restore the axonal transport defects in patient-derived MNs.

Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis.

BackgroundMutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients’ fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures.ResultsHere, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts.ConclusionsThus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0075-6) contains supplementary material, which is available to authorized users.

Super-Resolution Microscopy Reveals Presynaptic Localization of the ALS/FTD Related Protein FUS in Hippocampal Neurons.

Fused in Sarcoma (FUS) is a multifunctional RNA-/DNA-binding protein, which is involved in the pathogenesis of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A common hallmark of these disorders is the abnormal accumulation of mutated FUS protein in the cytoplasm. Under normal conditions FUS is confined to the nuclear compartment, in neurons, however, additional somatodendritic localization can be observed. In this study, we carefully analyzed the subcellular localization of endogenous FUS at synaptic sites of hippocampal neurons which are among the most affected cell types in FTD with FUS pathology. We could confirm a strong nuclear localization of FUS as well as its prominent and widespread neuronal expression throughout the adult and developing rat brain, particularly in the hippocampus, the cerebellum and the outer layers of the cortex. Intriguingly, FUS was also consistently observed at synaptic sites as detected by neuronal subcellular fractionation as well as by immunolabeling. To define a pre- and/or postsynaptic localization of FUS, we employed super-resolution fluorescence localization microscopy. FUS was found to be localized within the axon terminal in close proximity to the presynaptic vesicle protein Synaptophysin1 and adjacent to the active zone protein Bassoon, but well separated from the postsynaptic protein PSD-95. Having shown the presynaptic localization of FUS in the nervous system, a novel extranuclear role of FUS at neuronal contact sites has to be considered. Since there is growing evidence that local presynaptic translation might also be an important mechanism for plasticity, FUS – like the fragile X mental retardation protein FMRP – might act as one of the presynaptic RNA-binding proteins regulating this machinery. Our observation of presynaptic FUS should foster further investigations to determine its role in neurodegenerative diseases such as ALS and FTD.

Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons

Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration. However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. We found that the ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under oxidative stress, leading to a disruption in the release of FUS from SGs in cultured neurons. Autophagy controls the quality of proteins or organelles; therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5−/− mouse embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, FUS(R521C) expression did not significantly impair autophagic degradation. Moreover, autophagy activation with rapamycin reduced the accumulation of FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced neurite fragmentation and cell death in neurons expressing mutant FUS under oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS associated with a FUS mutation under oxidative stress, as well as therapeutic insight regarding FUS pathology associated with excessive SGs.

Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis

Fused in sarcoma (FUS) is mutated in both sporadic amyotrophic lateral sclerosis (ALS) and familial ALS patients. The mechanisms underlying neurodegeneration are not fully understood, but FUS redistributes from the nucleus to the cytoplasm in affected motor neurons, where it triggers endoplasmic reticulum (ER) stress. Ataxin-2 is a polyglutamine protein which normally contains 22 repeats, but expanded repeats (>34) are found in Spinocerebellar Ataxia type 2. Recently ataxin-2 with intermediate length repeats (27-33) was found to increase the risk of ALS. Here we show that ataxin-2 with an ALS-linked intermediate length repeat (Q31) is a potent modifier of FUS pathology in cellular disease models. Translocation of FUS to the cytoplasm and ER stress were significantly enhanced by co-expression of mutant FUS with ataxin-2 Q31. Ataxin-2 also co-localized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, co-precipitated with FUS in ALS spinal cord lysates, and co-localized with FUS in the ER-Golgi compartments in neuronal cell lines. Fragmentation of the Golgi apparatus is linked to neurodegeneration in ALS and here we show that Golgi fragmentation is induced in cells expressing mutant FUS. Moreover, Golgi fragmentation was enhanced, and the early stages of apoptosis were triggered, when ataxin-2 Q31 was co-expressed with mutant FUS. These findings describe new cellular mechanisms linking ALS with ataxin-2 intermediate length polyQ expansions and provide further evidence linking disruption to ER-Golgi compartments and FUS pathology in ALS.

The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients

RNA-binding protein pathology now represents one of the best characterized pathologic features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration patients with TDP-43 or FUS pathology (FTLD-TDP and FTLD-FUS). Using liquid chromatography tandem mass spectrometry, we identified altered levels of the RNA-binding motif 45 (RBM45) protein in the cerebrospinal fluid (CSF) of ALS patients. This protein contains sequence similarities to TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) that are contained in cytoplasmic inclusions of ALS and FTLD-TDP or FTLD-FUS patients. To further characterize RBM45, we first verified the presence of RBM45 in CSF and spinal cord tissue extracts of ALS patients by immunoblot. We next used immunohistochemistry to examine the subcellular distribution of RBM45 and observed in a punctate staining pattern within nuclei of neurons and glia in the brain and spinal cord. We also detected RBM45 cytoplasmic inclusions in 91 % of ALS, 100 % of FTLD-TDP and 75 % of Alzheimer’s disease (AD) cases. The most extensive RBM45 pathology was observed in patients that harbor the C9ORF72 hexanucleotide repeat expansion. These RBM45 inclusions were observed in spinal cord motor neurons, glia and neurons of the dentate gyrus. By confocal microscopy, RBM45 co-localizes with ubiquitin and TDP-43 in inclusion bodies. In neurons containing RBM45 cytoplasmic inclusions we often detected the protein in a punctate pattern within the nucleus that lacked either TDP-43 or ubiquitin. We identified RBM45 using a proteomic screen of CSF from ALS and control subjects for candidate biomarkers, and link this RNA-binding protein to inclusion pathology in ALS, FTLD-TDP and AD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-1045-x) contains supplementary material, which is available to authorized users.

Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats

Ubiquitin-positive inclusion containing Fused in Sarcoma (FUS) defines a new subtype of frontotemporal lobar degeneration (FTLD). FTLD is characterized by progressive alteration in cognitions and it preferentially affects the superficial layers of frontotemporal cortex. Mutation of FUS is linked to amyotrophic lateral sclerosis and to motor neuron disease with FTLD. To examine FUS pathology in FTLD, we developed the first mammalian animal model expressing human FUS with pathogenic mutation and developing progressive loss of memory. In FUS transgenic rats, ubiquitin aggregation and FUS mislocalization were developed primarily in the entorhinal cortex of temporal lobe, particularly in the superficial layers of affected cortex. Overexpression of mutant FUS led to Golgi fragmentation and mitochondrion aggregation. Intriguingly, aggregated ubiquitin was not colocalized with either fragmented Golgi or aggregated mitochondria, and neurons with ubiquitin aggregates were deprived of endogenous TDP-43. Agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) possess anti-glial inflammation effects and are also shown to preserve the dendrite and dendritic spines of cortical neurons in culture. Here we show that rosiglitazone, a PPAR-γ agonist, rescued the dendrites and dendritic spines of neurons from FUS toxicity and preserved rats' spatial memory. Our FUS transgenic rats would be useful to the mechanistic study of cortical dementia in FTLD. As rosiglitazone is clinically used to treat diabetes, our results would encourage immediate application of PPAR-γ agonists in treating patients with cortical dementia.

Clinical characterization of bvFTD due to FUS neuropathology

In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social–emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social– emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and diminished capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD.

TDP-43 pathology occurs infrequently in multiple system atrophy

The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological 43-kDa transactive response DNA-binding protein (TDP-43) or fused in sarcoma (FUS) aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein-mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.

Very early-onset frontotemporal dementia with no family history predicts underlying fused in sarcoma pathology

Sir, Neumann et al . (2009) recently described a new subtype of frontotemporal lobar degeneration (FTLD). They examined 15 cases of FTLD with inclusions that stained positive for ubiquitin (FTLD-U) but not transactive response DNA-binding protein (TDP-43), and found positive staining for the fused in sarcoma (FUS) protein in all cases. Interestingly, this case series was also characterized by an early age of onset and absence of family history. The mean age of onset was 38 years, and 12 out of the 15 cases had an age of onset of ≤40 years (Mackenzie et al. , 2008; Roeber et al. , 2008). Since this early age of onset is highly unusual for frontotemporal dementia (Neary et al. , 2005), we hypothesized that an age of onset at ≤40 years, in the absence of a family history, could also predict underlying FUS pathology. We tested this hypothesis by reviewing the Sydney Brain Bank. …