Mutations in C9ORF72 resulting in expanded hexanucleotide repeats were recently reported to be the underlying genetic abnormality in chromosome 9p-linked frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kD (TDP-43) proteinopathy (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). Several subsequent publications described the neuropathology as being similar to that seen in cases of FTLD-TDP and ALS without C9ORF72 mutations, except that cases with mutations have p62 and ubiquitin positive, TDP-43 negative inclusions in cerebellum, hippocampus, neocortex, and basal ganglia. The identity of this protein is as yet unknown, and its significance is unclear. With the goal of potentially uncovering the significance of these TDP-43 negative inclusions, we compared the clinical, pathologic, and genetic characteristics in 5 cases of FTLD-TDP and FTLD-MND with C9ORF72 mutations to 20 cases without mutations. We confirmed the apparent specificity of p62 positive, TDP-43 negative inclusions in cerebellum, hippocampus, cortex, and basal ganglia to FTLD with C9ORF72 mutations. p62 positive, TDP-43 negative inclusions in hippocampus correlated with hippocampal atrophy, but no additional correlations were uncovered. However, although ambiguity of TDP sub-typing has previously been reported in cases with C9ORF72 mutations, this is the first report to show that although most FTLD cases with C9ORF72 mutations were TDP type B, some of the pathologic characteristics in these cases were more similar to TDP types A and C than to TDP type B FTLD cases without mutations. These features include greater cortical and hippocampal atrophy, greater ventricular dilatation, more neuronal loss and gliosis in temporal lobe and striatum, and TDP-43 positive fine neuritic profiles in the hippocampus in FTLD cases with C9ORF72 mutations compared to FTLD-TDP type B cases without mutations, implying that the C9ORF72 mutation modifies the pathologic phenotype of FTLD-TDP type B.
C9ORF72; repeat expansion; p62; ubiquitin; TDP-43; FTLD; ALS
FTLD-TDP; FTLD-FUS; ALS; TDP-43; amyloid; prion; thioflavin
Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial FTLD with ubiquitinated inclusions have mutations in the progranulin gene, located on chromosome 17. It is also clear that most ubiquitinated inclusions in FTLD with ubiquitinated inclusions are composed primarily of TAR DNA-binding protein-43. Thus, FTLDs can be separated into 2 major groups (i.e. tauopathies and ubiquitinopathies), and most of the ubiquitinopathies can now be defined as TAR DNA-binding protein-43 proteinopathies. Many of the familial FTLDs are linked to chromosome 17, including both the familial tauopathies and the familial TAR DNA-binding protein-43 proteinopathies with progranulin mutations. This review highlights the neuropathologic features and the most important discoveries of the last 2 years and places these findings into the historical context of FTLD.
Frontotemporal lobar degeneration; FTDP-17; FTLD-U; Progranulin; TAR-DNA binding protein-43; Tauopathy; Ubiquitinopathy
globular glial tauopathy; globular oligodendroglial inclusions; dementia; Alzheimer disease; neuropsychological testing
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
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C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
A 56-year-old woman presented with changes in balance, handwriting, and thinking. Approximately 1 year before her first visit, the patient developed difficulty walking, which caused multiple falls without serious injury. She also developed bilateral upper-extremity tremors that worsened with movement. At the time of her visit, she could barely sign her name.
Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
We aimed to investigate the role of the nuclear carrier and binding proteins, transportin-1 (TRN1) and transportin-2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing’s Sarcoma protein (EWS) in inclusion body formation in cases of Frontotemporal Lobar Degeneration (FTLD) associated with Fused in Sarcoma protein (FTLD-FUS).
Eight cases of FTLD-FUS (5 cases of atypical FTLD-U (aFTLD-U), 2 of Neuronal Intermediate Filament Inclusion Body Disease (NIFID) and 1 of Basophilic Inclusion Body Disease (BIBD)) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. 10 cases of FTLD associated with TDP-43 inclusions served as reference cases.
The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD.
Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
Frontotemporal Lobar degeneration; Fused in Sarcoma; TDP-43; transportins; TATA-binding protein-associated factor 15; Ewing’s sarcoma protein
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the morphologic hallmark of Pick disease. Pick disease is a type of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD. The 2 major categories of pathologic FTLD are tauopathies (FTLD-tau) and ubiquitinopathies (FTLD-U). Pick disease is one of the FTLD-tau subtypes and is termed FTLD-tau (PiD).
To “demystify” FTLDs, and to demonstrate that subtypes of FTLD-tau and FTLD-U can be easily determined by following a logical, stepwise, histochemical, and immunohistochemical investigation of the FTD autopsy brain.
Previously published peer-reviewed articles.
The hope is that this article will be a useful reference for the general pathologist faced with performing a brain autopsy on a decedent with frontotemporal dementia.
Cis-trans isomerization of proteins phosphorylated by proline-directed kinases is proposed to control numerous signaling molecules, and is implicated in the pathogenesis of Alzheimer’s and other diseases. However, there is no direct evidence for the existence of cis-trans protein isomers in vivo, or for their conformation-specific function or regulation. Here we develop peptide chemistries that allow the generation of cis and trans-specific antibodies, and use them to raise antibodies specific for isomers of phosphorylated tau. Cis, but not trans, p-tau appears early in the brains of humans with mild cognitive impairment, and accumulates exclusively in degenerated neurons and localizes to dystrophic neurites during Alzheimer’s progression. Unlike trans p-tau, the cis isomer cannot promote microtubule assembly, is more resistant to dephosphorylation and degradation, and is more prone to aggregation. Pin1 converts cis to trans p-tau to prevent Alzheimer’s tau pathology. Isomer-specific antibodies and vaccines may therefore have value for the early diagnosis and treatment of Alzheimer’s disease
Mutations in the Fused in sarcoma/Translated in liposarcoma gene (FUS/TLS, FUS) have been identified among patients with amyotrophic lateral sclerosis (ALS). FUS protein aggregation is a major pathological hallmark of FUS proteinopathy, a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies. We prepared transgenic Drosophila expressing either the wild type (Wt) or ALS-mutant human FUS protein (hFUS) using the UAS-Gal4 system. When expressing Wt, R524S or P525L mutant FUS in photoreceptors, mushroom bodies (MBs) or motor neurons (MNs), transgenic flies show age-dependent progressive neural damages, including axonal loss in MB neurons, morphological changes and functional impairment in MNs. The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy, representing the first stable animal model for this group of devastating diseases.
frontotemporal lobar degeneration (FTLD); FUS proteinopathy; animal model; amyotrophic lateral sclerosis; neurodegeneration
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
Aging; Alzheimer disease; Amyloid; Dementia; Epidemiology; Neuropathology; MAPT; Neurofibrillary tangles
The current consensus criteria for the neuropathologic diagnosis of Alzheimer’s disease (AD), known as the National Institute on Aging/Reagan Institute of the Alzheimer Association Consensus Recommendations for the Postmortem Diagnosis of AD or NIA-Reagan Criteria , were published in 1997 (hereafter referred to as “1997 Criteria”). Knowledge of AD and the tools used for clinical investigation of cognitive impairment and dementia have advanced substantially since then and have prompted this update on the neuropathologic assessment of AD.
We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (i) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (ii) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (iii) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. α-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, α-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, α-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer's disease, Lewy body diseases, and motor neuron disease also contain epitopes of α-internexin. Thus, α-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of α-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions.
α-Internexin; Neurofilament; Intermediate filament; Neuronal intermediate filament inclusion disease; Frontotemporal dementia
Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5–10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.
Frontotemporal lobar degeneration; Motor neurone disease; Microtubule associated protein; Tau; TDP-43; FUS; Gain of function; Loss of function
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
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 FTLD 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 α-internexin and neurofilament proteins. Herein, we have: (1) shown that FUS becomes relatively insoluble in NIFID and there are no post-translational modifications; (2) shown there are no pathogenic abnormalities in the FUS gene in NIFID; (3) performed an immunoelectron microscopy analysis of the precise localizations of FUS in NIFID, as this 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’ (LACI), 81% of which had moderate or high levels of FUS-immunoreactivity. Much rarer ‘compact cytoplasmic inclusions’ (CCI) and ‘Tangled twine ball inclusions’ (TTBI) 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.
Neuronal intermediate filament inclusion disease; frontotemporal lobar degeneration; FUS; neurofilament; α-internexin; immunoelectron microscopy
Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS).
To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1-linked ALS.
Clinical case series.
Academic referral center.
We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z.
We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z.
The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non-SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS.
Mutations in TARDBP, encoding TAR DNA-binding protein-43 (TDP-43), are associated with TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We compared wild-type TDP-43 and an ALS-associated mutant TDP-43 in vitro and in vivo. The A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease-resistant fragments. The C terminus of TDP-43 shows sequence similarity to prion proteins. Synthetic peptides flanking residue 315 form amyloid fibrils in vitro and cause neuronal death in primary cultures. These data provide evidence for biochemical similarities between TDP-43 and prion proteins, raising the possibility that TDP-43 derivatives may cause spreading of the disease phenotype among neighboring neurons. Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies.
The goal of this study was to determine if the apolipoprotein ε (ApoE) gene, which is a well-established susceptibility factor for Alzheimer’s disease (AD) pathology in typical amnestic dementias, may also represent a risk factor in the language-based dementia, primary progressive aphasia (PPA). Apolipoprotein E genotyping was obtained from 149 patients with a clinical diagnosis of PPA, 330 cognitively healthy individuals (NC) and 179 patients with a clinical diagnosis of probable Alzheimer’s disease (PrAD). Allele frequencies were compared among the groups. Analyses were also completed by gender and in two subsets of PPA patients, one where patients were classified by subtype (logopenic, agrammatic and semantic) and another where pathologic data were available. The allele frequencies for the PPA group (ε2:5%, ε3:79.5%, and ε4:15.4%) showed a distribution similar to the NC group but significantly different from the PrAD group. The presence of an ε4 allele did not influence the age of symptom onset or aid in the prediction of AD pathology in PPA. These data show that the ε4 polymorphism, which is a well-known risk factor for AD pathology in typical amnestic dementias, has no similar relationship to the clinical syndrome of PPA or its association with AD pathology.