Familial Frontotemporal Lobar Degeneration Research Articles

Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases

A great deal has been written about cognitive aspects of semantic dementia but little is known about the demography or prognosis. We describe these features in a consecutive series of 100 patients seen over a 17-year period; all cases were assessed and followed up in a specialist clinic. The mean age at diagnosis was 64.2 (+/-7.1) range 40-79 years, but 46 presented after age 65 and 7 after 75; a higher proportion than the existing literature might predict. Fifteen had a first-degree relative with dementia, but in seven this was almost certainly unrelated. Only two had relatives with young-onset dementia. There were no families with more than two affected members. The familial rate was estimated at between 2% and 7% (95% confidence interval 0-12%). Kaplan-Meier analyses indicated a 50% survival of 12.8 years (95% confidence interval 11.9-13.7); a more benign course than suggested by neuropathologically based studies. We were unable to identify any factors influencing survival. Of the 100, 34 have died, with pathological confirmation in 24; 18 had frontotemporal lobar degeneration with ubiquitin-positive inclusions (13 of 13 confirmed TAR DNA binding protein-43 positive), and 3 had classic tau-positive Pick bodies and 3 had Alzheimer's pathology. The age at diagnosis or death across the pathological subgroups was equivalent. Although semantic dementia has a strong statistical association with ubiquitin-positive pathology, it does not have the signature of familial frontotemporal lobar degeneration with ubiquitin-positive inclusions, notably the presence of intranuclear lentiform TAR DNA binding protein-43 inclusions. The age of onset is older than predicted and the course more slowly progressive than suggested by earlier studies of small groups of subjects.

Absence of TARDBP Gene Mutations in an Italian Series of Patients with Frontotemporal Lobar Degeneration

Background/Aim: Recent studies showed that TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, is a major pathological protein in both sporadic and familial frontotemporal lobar degeneration (FTLD). The aim of this study was to search for mutations of the TARDBP gene in the disease. Methods: We sequenced the TARDBP gene in 172 unrelated FTLD patients recruited from 2 Italian memory clinics. Results: We identified 3 different variants of the TARDBP gene in 12 FTLD patients. Three patients showed a silent variant, Ala66Ala (c.332T → C) in exon 2. A novel heterozygous mutation was found in intron 4 (c.543 + 51A → G) in 1 patient, which is not located at the splicing site. Finally, a c.208C → T variant in the 3′ untranslated region was detected in 8 probands. None of the aforementioned variants were predicted to affect TDP-43. Hence, pathogenic mutations were not identified in any of the FTLD cases. Conclusion: Our study, in accord with previous studies in different populations, found no evidence for a major genetic role of the TARDBP gene in FTLD.

Frontotemporal lobar degeneration with ubiquitinated tau‐negative inclusions and additional α‐synuclein pathology but also unusual cerebellar ubiquitinated p62‐positive, TDP‐43‐negative inclusions

Mutations in the progranulin (PGRN) gene on chromosome 17 have been shown to be responsible for one non-tauopathy subtype of familial frontotemporal lobar degeneration - frontotemporal lobar degeneration with ubiquitinated, tau-negative inclusions (FTLD-U). Such cases have pathological similarities to sporadic cases with neuronal inclusions positive for ubiquitin, the ubiquitin binding protein, p62 and the newly recognised protein TDP-43 but negative for hyperphosphorylated (HP) tau. There has been a recent report on two families with a novel progranulin mutation where the neuropathology showed not only TDP-43 neuronal positivity but separate tau and/or alpha-synuclein pathology. We describe an unusual case with some family history but no mutation in the progranulin gene. The pathological features were typical for FTLD-U but with additional significant alpha-synuclein pathology, and unusual ubiquitin-positive, p62-positive, TDP-43-negative inclusions in the cerebellum. This case may represent a further pathological phenotype for familial FTLD-U. It also highlights the need for further investigations on the ubiquitin binding protein p62 as a marker in FTLD-U. It is certainly possible that the presence or absence of these ubiquitinated p62-positive yet TDP-43-negative cerebellar inclusions may act as a useful correlative factor in the future.

Identification of three novel progranulin mutations in a series of patients affected by sporadic and familial frontotemporal lobar degeneration

Identification of three novel progranulin mutations in a series of patients affected by sporadic and familial frontotemporal lobar degeneration

TDP-43 pathology in familial British dementia

Trans-activation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. This has suggested defining a new class of diseases known as TDP-43 proteinopathies. However, it has been reported more recently that TDP-43 positive inclusions occur in other neurodegenerative disorders such as Alzheimer's disease, Dementia with Lewy Bodies and Parkinsonism dementia complex of Guam. Here we report the occurrence of TDP-43 inclusions in one other neurodegenerative disorder: familial British dementia. Using a variety of antibodies against phosphorylated and non-phosphorylated TDP-43 epitopes, we found intense accumulation occurred in the form of dystrophic neurites, neuronal cytoplasmic inclusions and was also occasionally associated with neurofibrillary tangles. Double immunostaining revealed that TDP-43 and tau aggregates were rarely directly colocalized, but co-existed in the same neurons as separate inclusions. Double staining with ubiquitin showed a direct colocalization with TDP-43. The phosphorylation-dependent TDP-43 antibodies proved superior to phosphorylation-independent antibodies in revealing pathological inclusions since the former did not stain non-phosphorylated TDP-43 in normal nuclei. Our results support the concept that TDP-43 pathology is not narrowly restricted, but is involved in the etiology of many neurodegenerative disorders.

Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies

The disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) was identified recently as the TDP-43 (TAR DNA-binding protein 43), thereby providing a molecular link between these two disorders. In FTLD-U and ALS, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate C-terminal fragments (CTFs). However, the specific cleavage site(s) and the biochemical properties as well as the functional consequences of pathological TDP-43 CTFs remained unknown. Here we have identified the specific cleavage site, Arg(208), of a pathological TDP-43 CTF purified from FTLD-U brains and show that the expression of this and other TDP-43 CTFs in cultured cells recapitulates key features of TDP-43 proteinopathy. These include the formation of cytoplasmic aggregates that are ubiquitinated and abnormally phosphorylated at sites found in FTLD-U and ALS brain and spinal cord samples. Furthermore, we observed splicing abnormalities in a cell culture system expressing TDP-43 CTFs, and this is significant because the regulation of exon splicing is a known function of TDP-43. Thus, our results show that TDP-43 CTF expression recapitulates key biochemical features of pathological TDP-43 and support the hypothesis that the generation of TDP-43 CTFs is an important step in the pathogenesis of FTLD-U and ALS.

Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 ( UBAP1; OR 1.42 95% CI 1.08–1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04–1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02–1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97–2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72–1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.

Molecular Neuropathology of TDP-43 Proteinopathies

The identification of TDP-43 as the major component of the pathologic inclusions in most forms of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein under these conditions. Anti-TDP-43 immunohistochemistry and the recent development of novel tools, such as phosphorylation-specific TDP-43 antibodies, have increased our knowledge about the spectrum of pathological changes associated with FTLD-U and ALS and moreover, facilitated the neuropathological routine diagnosis of these conditions. This review summarizes the recent advances in our understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.

Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide

Mutations in the progranulin gene ( PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T > C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C > T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.

Colocalization of Transactivation-Responsive DNA-Binding Protein 43 and Huntingtin in Inclusions of Huntington Disease

Transactivation-responsive DNA-binding protein 43 (TDP-43) is a component of pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familial frontotemporal lobar degeneration. Transactivation-responsive DNA-binding protein 43-immunostained inclusions have also been found in other neurodegenerative disorders including Alzheimer disease, dementia with Lewy bodies, and parkinsonism dementia complex of Guam. Here, we analyzed the occurrence of TDP-43 immunostaining in Huntington disease, which is characterized by inclusions containing mutated huntingtin. In all Huntington disease cases studied, TDP-43 was frequently colocalized with huntingtin in dystrophic neurites and various intracellular inclusions, but not in intranuclear inclusions; the latter were only stained with huntingtin and anti-ubiquitin antibodies. Two phosphorylation-dependent TDP-43 antibodies proved to be superior for detecting pathological inclusions because they did not stain nonphosphorylated TDP-43 in normal nuclei; staining of normal nuclei with phosphorylation-independent antibodies obscured the inclusions. Our results further add to the hypothesis that TDP-43 may be involved in the pathology of a variety of neurodegenerative disorders.

Enrichment of C-Terminal Fragments in TAR DNA-Binding Protein-43 Cytoplasmic Inclusions in Brain but not in Spinal Cord of Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

TAR DNA-binding protein (TDP-43) has been recently described as a major pathological protein in both frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. However, little is known about the relative abundance and distribution of different pathological TDP-43 species, which include hyperphosphorylated, ubiquitinated, and N-terminally cleaved TDP-43. Here, we developed novel N-terminal (N-t) and C-terminal (C-t)-specific TDP-43 antibodies and performed biochemical and immunohistochemical studies to analyze cortical, hippocampal, and spinal cord tissue from frontotemporal dementia with ubiquitin-positive inclusions and amyotrophic lateral sclerosis cases. C-t-specific TDP-43 antibodies revealed similar abundance, morphology, and distribution of dystrophic neurites and neuronal cytoplasmic inclusions in cortex and hippocampus compared with previously described pan-TDP-43 antibodies. By contrast, N-t-specific TDP-43 antibodies only detected a small subset of these lesions. Biochemical studies confirmed the presence of C-t TDP-43 fragments but not extreme N-t fragments. Surprisingly, immunohistochemical analysis of inclusions in spinal cord motor neurons in both diseases showed that they are N-t and C-t positive. TDP-43 inclusions in Alzheimer's disease brains also were examined, and similar enrichment in C-t TDP-43 fragments was observed in cortex and hippocampus. These results show that the composition of the inclusions in brain versus spinal cord tissues differ, with an increased representation of C-t TDP-43 fragments in cortical and hippocampal regions. Therefore, regionally different pathogenic processes may underlie the development of abnormal TDP-43 proteinopathies.

Update on Recent Molecular and Genetic Advances in Frontotemporal Lobar Degeneration

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.

P2-184: Identification of a novel chromosomal locus in a Belgian FTLD-MND family

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative brain disorder with a prevalence similar to that of Alzheimer's disease in the population below age 65 years. In some patients FTLD symptoms are accompanied by signs of motor neuron disease (MND). A positive family history is observed in up to 50% of FTLD patients indicating a significant contribution of genetics to the etiology of FTLD. A high degree of genetic heterogeneity has been observed with different mutations in the genes encoding the microtubule-associated protein (MAPT), progranulin (PGRN), charged multivesicular body protein 2B (CHMP2B) and valosin containing protein (VCP). Further, two loci on chromosome 9 at 9q21-q22 and 9p13–21 were implicated in FTLD with MND (FTLD-MND). In Belgian familial FTLD patients 65% remained unexplained by mutations in known FTLD genes. Of one patient diagnosed with FTLD-MND, we collected DNA of relatives and performed a genome-wide scan. We identified and finemapped a novel chromosomal locus that was not previously linked to FTLD and/or MND. Haplotype analysis identified a risk haplotype of 23 cM that co-segregated with disease. Further reduction of the candidate region and mutation analyses of positional and functional candidate genes are ongoing. Identification of the mutation in the underlying disease gene will significantly contribute to the understanding of neurodegenerative disease mechanisms in FTLD.

An alternative in vitro model of neurodegeneration in FTLD‐U with PGRN mutation

Recently, the gene for familial frontotemporal lobar degeneration with ubiquitin‐positive, tau‐negative inclusions (FTLD‐U) linked to chromosome 17 was cloned. In the present study, 42 unrelated patients from the Washington University Alzheimer's Disease Research Center (WUADRC) with clinically diagnosed FTLD and/or neuropathologically characterized cases of FTLD‐U with or without MND were screened for mutations in PGRN. Bidirectional sequencing was performed for mutational screening. Mechanistically, most mutations in PGRN described thus far have been reported to display a haploinsufficiency through nonsense mediated decay (NMD). We describe a novel missense mutation in exon 1 (c.4068 C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (A9D) which displayed no significant difference in the total postmortem brain PGRN mRNA between cases and controls. In SHSY‐5Y neuroblastoma cells overexpressed with mutant or wild‐type PGRN, subcellular fractionation, biochemistry, and confocal microscopy indicate that mutant protein is expressed, but is not processed, through the ER for secretion, and appears to be misslocalized in the cytosol possibly resulting in a functional haploinsufficiency. This defect in trafficking results in a decrease in cell viability: an alternative in vitro model of FTLD‐U with PGRN mutation neurodegeneration. Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health (P01‐AG03991, P50‐AG05681) and the Buchanan Fund.

Establishment of a stable progranulin deficient cell line: a model of frontotemporal dementia with ubiquitin‐positive inclusions

Mutations in the gene coding for progranulin (PGRN) are responsible for many cases of familial frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U). Mutations in progranulin create null alleles resulting in decreased progranulin protein or haploinsufficiency, which leads to reduced PGRN‐mediated neuronal survival. In order to elucidate the molecular mechanisms involved in the pathogenesis of FTLD‐U, a cell line stably expressing shRNA against PGRN (shPGRN) under the control of tetracycline was established. HEK 293 cells were transfected with H1‐driven shPGRNs and progranulin‐expressing plasmids and effective shPGRNs were screened by Western blot. Human neuroblastoma SHSY5Y cells transfected with shPGRN expressing vector were found to have decreased cell growth rate and mitosis, and redistribution of TDP‐43 protein to cytoplasm. A line of SHSY5Y cells stably expressing shPGRN under the control of tetracycline (Tet on system) was established. The results indicate that it is feasible to establish a stable progranulin deficient mammalian cell line, which will be a powerful tool to study the pathogenesis of FTLD‐U and explore its potential treatments. The study was supported by NIH ADC grant AG12300, the UT Southwestern Friends of the Alzheimer's Disease Center, the Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, and the McCune Foundation.

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3' splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

Mutations in Progranulin Gene: Clinical, Pathological, and Ribonucleic Acid Expression Findings

There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.

CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro

The charged multivesicular body protein 2B gene (CHMP2B) was recently associated with frontotemporal lobar degeneration (FTLD) linked to chromosome 3 in a Danish FTLD family (FTD-3). In this family, a mutation in the acceptor splice site of exon 6 produced two aberrant transcripts predicting two C-truncated CHMP2B proteins due to a read through of intron 5 (p.Met178ValfsX2) and a cryptic splicing event within exon 6 (p.Met178LeufsX30). Extensive mutation analysis of CHMP2B in Belgian patients (N = 146) identified one nonsense mutation in exon 5 (c.493C>T) in a familial FTLD patient, predicting a C-truncated protein p.Gln165X analogous to the Danish mutant proteins. Overexpression of Belgian p.Gln165X in human neuroblastoma SK-N-SH cells showed the formation of large, aberrant endosomal structures that were highly similar to those observed for Danish p.Met178ValfsX2. Together, these data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in FTLD by disturbing endosome function. We also describe a missense mutation in exon 5 of CHMP2B (p.Asn143Ser) in a familial patient with cortical basal degeneration. However, the pathogenic character of this mutation remains elusive.

Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

TDP-43 proteinopathies: a new class of proteinopathies

The recent identification of TAR-DNA-binding protein-43 (TDP-43) as the major component of the pathologic inclusions characteristic to sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), as well as most forms of amyotrophic lateral sclerosis (ALS), resolved a long-standing enigma concerning the nature of the ubiquitinated disease protein in these conditions and provides further evidence that ALS and FTLD-U represent a clinicopathological spectrum of neurodegenerative disorders that share similar pathomechanisms. Although the physiological function of TDP-43 in the brain and its specific role in FTLD-U and ALS pathogenesis is currently unknown, the presence of ubiquitinated, hyperphosphorylated and truncated species of TDP-43, in addition to redistribution of physiological TDP-43 from the nucleus to cytoplasmic inclusions, implicates TDP-43 in a novel and unifying mechanism of neurodegeneration in TDP-43 proteinopathies. In this review, we summarize the identification of TDP-43 and the advances in understanding TDP-43 proteinopathies, and finally we discuss the implications of these discoveries for future strategies in developing diagnostics and therapeutics for FTLD-U and ALS.