Truncated TDP-43 proteoforms diagnostic of frontotemporal dementia with TDP-43 pathology.

INTRODUCTION: Biomarkers of TDP-43 pathology are needed to distinguish frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) from phenotypically related disorders. While normal physiological TDP-43 is not a promising biomarker, low-resolution techniques have suggested truncated forms of TDP-43 may be specific to TDP-43 pathology. To advance biomarker efforts for FTLD-TDP, we employed a high-resolution structural technique to characterize TDP-43 post-translational modifications in FTLD-TDP. METHODS: High-resolution mass spectrometry was used to characterize TDP-43 proteoforms in brain tissue from FTLD-TDP, non-TDP-43 dementias and neuropathologically unaffected cases. Findings were then verified in a larger cohort of FTLD-TDP and non-TDP-43 dementias via targeted quantitative mass spectrometry. RESULTS: In the discovery phase, truncated TDP-43 identified FTLD-TDP with 85% sensitivity and 100% specificity. The verification phase revealed similar findings, with 83% sensitivity and 89% specificity. DISCUSSION: The concentration of truncated TDP-43 proteoforms-in particular, in vivo generated C-terminal fragments-have high diagnostic accuracy for FTLD-TDP. HIGHLIGHTS: Discovery: Truncated TDP-43 differentiates FTLD-TDP from related dementias. Verification: Truncated TDP-43 concentration has high accuracy for FTLD-TDP. TDP-43 proteoforms <28 kDa have highest discriminatory power for TDP-43 pathology.

C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.

Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

White-matter abnormalities in presymptomatic GRN and C9orf72 mutation carriers.

A large proportion of familial frontotemporal dementia is caused by TAR DNA-binding protein 43 (transactive response DNA-binding protein 43 kDa) proteinopathies. Accordingly, carriers of autosomal dominant mutations in the genes associated with TAR DNA-binding protein 43 aggregation, such as Chromosome 9 open reading frame 72 (C9orf72) or progranulin (GRN), are at risk of later developing frontotemporal dementia. Brain imaging abnormalities that develop before dementia onset in mutation carriers may serve as proxies for the presymptomatic stages of familial frontotemporal dementia due to a genetic cause. Our study objective was to investigate brain MRI-based white-matter changes in predementia participants carrying mutations in C9orf72 or GRN genes. We analysed mutation carriers and their family member controls (noncarriers) from the University of British Columbia familial frontotemporal dementia study. First, a total of 42 participants (8 GRN carriers; 11 C9orf72 carriers; 23 noncarriers) had longitudinal T1-weighted MRI over ∼2 years. White-matter signal hypointensities were segmented and volumes were calculated for each participant. General linear models were applied to compare the baseline burden and the annualized rate of accumulation of signal abnormalities among mutation carriers and noncarriers. Second, a total of 60 participants (9 GRN carriers; 17 C9orf72 carriers; 34 noncarriers) had cross-sectional diffusion tensor MRI available. For each participant, we calculated the average fractional anisotropy and mean, radial and axial diffusivity parameter values within the normal-appearing white-matter tissues. General linear models were applied to compare whether mutation carriers and noncarriers had different trends in diffusion tensor imaging parameter values as they neared the expected age of onset. Baseline volumes of white-matter signal abnormalities were not significantly different among mutation carriers and noncarriers. Longitudinally, GRN carriers had significantly higher annualized rates of accumulation (estimated mean: 15.87%/year) compared with C9orf72 carriers (3.69%/year) or noncarriers (2.64%/year). A significant relationship between diffusion tensor imaging parameter values and increasing expected age of onset was found in the periventricular normal-appearing white-matter region. Specifically, GRN carriers had a tendency of a faster increase of mean and radial diffusivity values and C9orf72 carriers had a tendency of a faster decline of fractional anisotropy values as they reached closer to the expected age of dementia onset. These findings suggest that white-matter changes may represent early markers of familial frontotemporal dementia due to genetic causes. However, GRN and C9orf72 mutation carriers may have different mechanisms leading to tissue abnormalities.

Recent Advances in Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a devastating neurodegenerative condition for which there is currently no effective treatment. Although it is much less common than Alzheimer's disease, the impact of FTD is increased by its relatively early onset and high heritability. Clinical heterogeneity and overlap with other neurodegenerative and psychiatric syndromes complicate diagnosis. However, recent advances in our understanding of the molecular basis of FTD provide a foundation for the development of much-needed biomarkers and targeted therapies. This review provides a summary of the recently revised clinical criteria for FTD, highlights diagnostic challenges, briefly summarizes recent molecular discoveries and then focuses on promising developments in biomarkers and clinical trials.

Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging.

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population.

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Aptamer-based enrichment of TDP-43 from human cells and tissues with quantification by HPLC-MS/MS.

BACKGROUND: There is great interest in detecting, characterizing and quantifying transactive response DNA binding protein of 43 kDa (TDP-43), and its post-translational modifications, due to its association with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Unfortunately, detailed analysis of TDP-43 in human biological matrices by immunometric methods has been hindered by the relatively low abundance of TDP-43 and poor antibody reagent specificity. NEW METHOD: With the goal of developing a selective and multiplex method for characterizing TDP-43, we previously developed a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) assay for relative quantification of TDP-43 in human brain tissue and cells. To improve analytical sensitivity and to perform absolute quantification, we coupled a novel RNA-based aptamer enrichment workflow (and inclusion of a stable isotope-labeled standard) to HPLC-MS/MS. RESULTS: The TDP-43 aptamer-enrichment-HPLC-MS/MS assay was linear from 0.37 to 2.55nmol/L, a range suitable for analysis of both human cells and brain tissue homogenates, and had a total CV of 14.8%. Quantitative TDP-43 peptide profiles were developed for cases of FTD with TDP-43 pathology and cases with no neurodegenerative pathology. COMPARISON WITH EXISTING METHODS: Compared to immunoenrichment, aptamer-enrichment yielded cleaner recoveries of TDP-43. The aptamer-enrichment-HPLC-MS/MS method, compared to our previous method without enrichment, increased analytical sensitivity by 8.7-fold and 11.8-fold for endogenous TDP-43 in human cells and brain tissue, respectively. Critically, inclusion of the aptamer enrichment step improved sequence resolution and enabled identification of TDP-43 C-terminal fragments. CONCLUSIONS: The aptamer-enrichment-HPLC-MS/MS method enabled highly selective quantification, enhanced sequence coverage and structural characterization of endogenous TDP-43.

Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway.

Nucleocytoplasmic transport (NCT) decline occurs with aging and neurodegeneration. Here, we investigated the NCT pathway in models of amyotrophic lateral sclerosis-fused in sarcoma (ALS-FUS). Expression of ALS-FUS led to a reduction in NCT and nucleoporin (Nup) density within the nuclear membrane of human neurons. FUS and Nups were found to interact independently of RNA in cells and to alter the phase-separation properties of each other in vitro. FUS-Nup interactions were not localized to nuclear pores, but were enriched in the nucleus of control neurons versus the cytoplasm of mutant neurons. Our data indicate that the effect of ALS-linked mutations on the cytoplasmic mislocalization of FUS, rather than on the physiochemical properties of the protein itself, underlie our reported NCT defects. An aberrant interaction between mutant FUS and Nups is underscored by studies in Drosophila, whereby reduced Nup expression rescued multiple toxic FUS-induced phenotypes, including abnormal nuclear membrane morphology in neurons.

FDG-PET in presymptomatic C9orf72 mutation carriers.

OBJECTIVE: Our aim is to investigate patterns of brain glucose metabolism using fluorodeoxyglucose positron emission tomography (FDG-PET) in presymptomatic carriers of the C9orf72 repeat expansion to better understand the early preclinical stages of frontotemporal dementia (FTD). METHODS: Structural MRI and FDG-PET were performed on clinically asymptomatic members of families with FTD caused by the C9orf72 repeat expansion (15 presymptomatic mutation carriers, C9orf72+; 20 non-carriers, C9orf72-). Regional glucose metabolism in cerebral and cerebellar gray matter was compared between groups. RESULTS: The mean age of the C9orf72+ and C9orf72- groups were 45.3 ± 10.6 and 56.0 ± 11.0 years respectively, and the mean age of FTD onset in their families was 56 ± 7 years. Compared to non-carrier controls, the C9orf72+ group exhibited regional hypometabolism, primarily involving the cingulate gyrus, frontal and temporal neocortices (left > right) and bilateral thalami. CONCLUSIONS: The C9orf72 repeat expansion is associated with changes in brain glucose metabolism that are demonstrable up to 10 years prior to symptom onset and before changes in gray matter volume become significant. These findings indicate that FDG-PET may be a particularly sensitive and useful method for investigating and monitoring the earliest stages of FTD in individuals with this underlying genetic basis.

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Applying the Alzheimer Disease ATN Diagnostic Framework in Atypical Dementia.

Cerebrospinal fluid (CSF) biomarkers amyloid-ß and tau have been validated for the antemortem diagnosis of Alzheimer disease (AD) and are included in the AT(N) research framework for AD. Recently, an AT(N) CSF profile has been described for dementia with Lewy bodies (DLB), a disorder which is difficult to distinguish clinically from AD, particularly early in the disease course. Herein we describe a 71-year old male who presented with an atypical dementia syndrome including years of stability after an initial abrupt decline, marked visuospatial dysfunction, and relative sparing of memory. CSF biomarkers combined with the pattern of cognitive symptoms made AD unlikely and were consistent with DLB. This classification was confirmed clinically, with the emergence of classic DLB symptoms, and at postmortem pathologic examination. This case highlights the role for AD CSF biomarkers in facilitating earlier diagnosis of non-Alzheimer neurodegenerative dementias.

TDP-43 pathology in primary lateral sclerosis.

Primary lateral sclerosis (PLS) is a controversial form of motor neuron disease (MND), with uncertainty whether it represents a distinct clinico-pathological entity or is simply a variant of classical amyotrophic lateral sclerosis (ALS). Neuropathological studies provide an opportunity to investigate these issues; however, there have been very few published descriptions of postmortem findings in clinically defined PLS, using modern techniques. Here, we report the neuropathological features of seven cases of PLS with age at onset ranging from 47 to 73 years and disease duration from 3.5 to 35 years. All cases showed chronic degeneration of the primary motor cortex and/or the corticospinal tracts with preservation of lower motor neurons (LMN). All five cases, in which motor cortex was available, had TDP-43 immunoreactive (TDP-ir) cortical pathology. In all seven cases, TDP-ir inclusions were also present in LMN; however, these were always rare, averaging less than one inclusion per tissue section. The finding of TDP-ir pathology in all our cases suggests that PLS and ALS are closely related conditions. Importantly however, the extremely minor involvement of LMN, even after very long disease duration in some cases, suggests that PLS is a distinct form of MND in which LMN are spared or protected.

Neuropathology of primary lateral sclerosis.

Published descriptions of the neuropathology of clinically defined primary lateral sclerosis (PLS) are reviewed in order to clarify the pathogenesis and the relationship between PLS and classical amyotrophic lateral sclerosis (ALS). Degeneration of the primary motor cortex and corticospinal tracts with preservation of lower motor neurons (LMN) has been reported in most cases. Studies that employed immunohistochemistry found ubiquitin and/or TDP-43-positive neuronal inclusions in the motor cortex and often in the extramotor neocortex. Ubiquitin/TDP-43-immunoreactive inclusions in LMN have been reported in just over half of cases; however, these have never been numerous. The finding of TDP-43 pathology in most cases indicates that PLS and ALS are closely related conditions; however, the fact that cases of PLS consistently show minimal involvement of LMN suggests that PLS represents a distinct entity, rather than an early stage of ALS.

Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers.

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Detection and characterization of TDP-43 in human cells and tissues by multiple reaction monitoring mass spectrometry.

Transactive response DNA-binding protein 43 kDa (TDP-43) is a highly conserved and widely expressed protein in human tissues that regulates nucleic acid processing. In frontotemporal dementia and amyotrophic lateral sclerosis, however, TDP-43 forms insoluble aggregates in central nervous tissues. These pathological deposits of TDP-43 have been primarily studied by ligand binding, namely western blot analysis, and, thus, methods with greater structural resolution are needed to aid in our understanding of the pathological processes associated with TDP-43 misfolding and aggregation. Toward this goal, we have developed a selective and multiplex method for the detection and characterization of TDP-43 using liquid chromatography tandem mass spectrometry. As proof-of-concept, the method was applied to the detection and characterization of TDP-43 in human cell lines and human brain tissue.

Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers.

Hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, but the pathogenic mechanism of this mutation remains unresolved. Haploinsufficiency has been proposed as one potential mechanism. However, insights if and how reduced C9orf72 proteins levels might contribute to disease pathogenesis are still limited because C9orf72 expression, localization and functions in the central nervous system (CNS) are uncertain, in part due to the poor specificity of currently available C9orf72 antibodies.Here, we generated and characterized novel knock-out validated monoclonal rat and mouse antibodies against C9orf72. We found that C9orf72 is a low abundant, cytoplasmic, highly soluble protein with the long 481 amino acid isoform being the predominant, if not exclusively, expressed protein isoform in mouse tissues and human brain. As consequence of the C9orf72 repeat expansion, C9orf72 protein levels in the cerebellum were reduced to 80% in our series of C9orf72 mutation carriers (n = 17) compared to controls (n = 26). However, no associations between cerebellar protein levels and clinical phenotypes were seen. Finally, by utilizing complementary immunohistochemical and biochemical approaches including analysis of human iPSC derived motor neurons, we identified C9orf72, in addition to its association to lysosomes, to be localized to the presynapses and able to interact with all members of the RAB3 protein family, suggestive of a role for C9orf72 in regulating synaptic vesicle functions by potentially acting as guanine nucleotide exchange factor for RAB3 proteins.In conclusion, our findings provide further evidence for haploinsufficiency as potential mechanism in C9orf72 pathogenesis by demonstrating reduced protein levels in C9orf72 mutation carriers and important novel insights into the physiological role of C9orf72 in the CNS. Moreover, the described novel monoclonal C9orf72 antibodies will be useful tools to further dissect the cellular and molecular functions of C9orf72.

Clinical and neuropathological features of ALS/FTD with TIA1 mutations.

Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

Fused in Sarcoma Neuropathology in Neurodegenerative Disease.

Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms.