Samir Kumar-Singh

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.

Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.

Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update

One year ago, in this journal, we published a recommended nomenclature for the neuropathologic subtypes of frontotemporal lobar degeneration (FTLD) [7]. A major impetus behind this was to resolve the confusion that had arisen around the use of the term “FTLD with ubiquitinated inclusions” (FTLD-U), following the discovery that the molecular pathology of these cases was heterogeneous, with most, but not all, being characterized by pathological TDP-43 [6, 11]. In addition, a system of nosology was introduced that grouped the FTLD subtypes into broad categories, based on the molecular defect that is most characteristic, according to current evidence. This system provided a concise and consistent terminology that has now been widely adopted in the literature. Another anticipated advantage was the ability to readily accommodate new discoveries. At the time, we did not anticipate how quickly this attribute would be put to use.

TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration.

Neuronal cytoplasmic and intranuclear aggregates of RNA-binding protein TDP-43 are a hallmark feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). ALS and FTLD show a considerable clinical and pathological overlap and occur as both familial and sporadic forms. Though missense mutations in TDP-43 cause rare forms of familial ALS, it is not yet known whether this is due to loss of TDP-43 function or gain of aberrant function. Moreover, the role of wild-type (WT) TDP-43, associated with the majority of familial and sporadic ALS/FTLD patients, is also currently unknown. Generating homozygous and hemizygous WT human TDP-43 transgenic mouse lines, we show here a dose-dependent degeneration of cortical and spinal motor neurons and development of spastic quadriplegia reminiscent of ALS. A dose-dependent degeneration of nonmotor cortical and subcortical neurons characteristic of FTLD was also observed. Neurons in the affected spinal cord and brain regions showed accumulation of TDP-43 nuclear and cytoplasmic aggregates that were both ubiquitinated and phosphorylated as observed in ALS/FTLD patients. Moreover, the characteristic ≈25-kDa C-terminal fragments (CTFs) were also recovered from nuclear fractions and correlated with disease development and progression in WT TDP-43 mice. These findings suggest that ≈25-kDa TDP-43 CTFs are noxious to neurons by a gain of aberrant nuclear function.

Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: Consensus recommendations

Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration : consensus recommendations

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.53–0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016

We identified a novel plasmid-mediated colistin-resistance gene in porcine and bovine colistin-resistant Escherichia coli that did not contain mcr-1. The gene, termed mcr-2, a 1,617 bp phosphoethanolamine transferase harboured on an IncX4 plasmid, has 76.7% nucleotide identity to mcr-1. Prevalence of mcr-2 in porcine colistin-resistant E. coli (11/53) in Belgium was higher than that of mcr-1 (7/53). These data call for an immediate introduction of mcr-2 screening in ongoing molecular epidemiological surveillance of colistin-resistant Gram-negative pathogens.

A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule‐associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy‐related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick‐type tauopathy in the absence of extracellular β‐amyloid deposits. The mutation is predicted to substitute Gly→Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical‐genetic investigation showed a positive family history of FTD‐like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick‐type tauopathy without MAPT mutations.

Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF ? expression

Vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF‐1 and ‐2), and transforming growth factor β (TGFβ) are potent angiogenic cytokines. Malignant mesothelioma of the pleura presents with a high intra‐tumoural microvascular density (IMD) which also has prognostic relevance. This study was designed to verify the immunohistochemical expression of the angiogenic cytokines in mesothelioma as well as in non‐neoplastic human mesothelial cells and to study the individual as well as the combined expression of these cytokines in mesothelioma in relation to both IMD and prognosis. In addition, four mesothelioma cell lines were studied by ELISA for the secretion of VEGF and FGF‐2 in their supernatants and were shown to contain high levels of both of these cytokines. Immunohistochemically, VEGF, FGF‐1 and ‐2, and TGFβ immunoreactivity was present in 81, 67, 92 and 96 per cent of mesotheliomas, and in 20, 50, 40, and 10 per cent of samples of the non‐neoplastic mesothelium, respectively. Co‐ordinate expression of the cytokines was observed whereby mesotheliomas expressed more than one cytokine. The combined immunohistochemical expression levels for all four cytokines correlated significantly with both IMD ( p=0·01) and prognosis ( p=0·0013). When studied individually, high FGF‐2 expression correlated best with more tumour aggressiveness and worse prognosis for mesothelioma ( p=0·0011). There was no significant correlation between prognosis and immunoexpression of VEGF ( p=0·07), FGF‐1 ( p=0·3), or TGFβ ( p=0·1), or between IMD and any of the cytokines studied individually. These data support the assertion that selective angiogenic cytokines might contribute to the progressive changes of mesothelioma by tumour angiogenesis. Copyright

Dense-Core Plaques in Tg2576 and PSAPP Mouse Models of Alzheimer’s Disease Are Centered on Vessel Walls

Occurrence of amyloid beta (Abeta) dense-core plaques in the brain is one of the chief hallmarks of Alzheimers disease (AD). It is not yet clear what factors are responsible for the aggregation of Abeta in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that approximately 95% of dense plaques in Tg2576 and approximately 85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Abeta, our data suggest that perturbed vascular transport and/or perivascular enrichment of Abeta leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD.

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by ps-1 mutations that lead to exceptionally high amyloid-β concentrations

We describe 3 new families affected by Alzheimers disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large “cotton wool” plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin‐1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Aβ42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid‐β concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimers disease and have implications for the pathogenesis of the disease in general. Ann Neurol 2000;48:806–808