Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nature Genet. 37, 806-808

University of Cambridge, Cambridge, England, United Kingdom
Nature Genetics (Impact Factor: 29.35). 09/2005; 37(8):806-8. DOI: 10.1038/ng1609
Source: PubMed


We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

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    • "A supervised clustering (heat map I-IV) was performed after mean-shift normalization of the data in order to highlight expression differences between these genes pre-and post-therapy (Fig. 1). Based on DAVID, all genes included in heat map I [Anikster et al., 2002; Iwamoto et al., 2004; Millar et al., 2005], heat map III [Labrada et al., 2002; Gardner and Ghorpade, 2003; Maisel et al., 2007; Sakamoto et al., 2007] and heat map IV [Jentsch, 1992; Zhang et al., 2004; Beasley et al., 2005; Wu, 2006; Han et al., 2007; Cicin-Sain et al., 2008; Simmen et al., 2008; Wegner et al., 2008; Le-Niculescu et al., 2009] were enriched significantly in various brain tissues (P I < 0.03; P III < 0.02; P IV < 0.01), while all genes included in heat map II [Spleiss et al., 1998; Ainiala et al., 2004; Hamilton et al., 2004; Millar et al., 2005; Skibinski et al., 2005; Georgieva et al., 2008] were associated significantly with a number of neuro-psychiatric symptoms or syndromes (P II < 0.01) (Fig. 1). Interestingly, 11 (52%) out of 21 selected genes were enriched significantly in CD4þ T-cells (P < 0.025) according to DA- VID (Supplementary Object 1). "
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    ABSTRACT: Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro-psychiatric symptoms. Pegylated-Interferon-α (PegIFN-α) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-α based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-α and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N=28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuro-psychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated-exonuclease-gene 20kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P<0.05) between three groups that were built by combining antiviral outcome and neuro-psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P<0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P<0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-α related neuro-psychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo. J. Med. Virol. 86:1323-1331, 2014.
    Full-text · Article · Aug 2014 · Journal of Medical Virology
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    • "Altered regulation of synaptic protein trafficking from early aberrant protein/peptide accumulation near synapses might lead to the earliest synapse dysfunction in neurodegenerative diseases [2]. Interestingly, mutations of CHMP2b, a component of ESCRTIII, have been linked with familial forms of FTD [27]. Although FTD, the 2nd most common cause of dementia before the age of 65, is not genetically linked with Aβ/APP, it has been linked to familial mutations in tau, the main constituent of the other characteristic neuropathology of AD, the neurofibrillary tangles. "
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    ABSTRACT: Age-related misfolding and aggregation of disease-linked proteins in selective brain regions is a characteristic of neurodegenerative diseases. Although neuropathological aggregates that characterize these various diseases are found at sites other than synapses, increasing evidence supports the idea that synapses are where the pathogenesis begins. Understanding these diseases is hampered by our lack of knowledge of what the normal functions of these proteins are and how they are affected by aging. Evidence has supported the idea that neurodegenerative disease-linked proteins have a common propensity for prion protein-like cell-to-cell propagation. However, it is not thought that the prion-like quality of these proteins/peptides that allows their cell-to-cell transmission implies a role for human-to-human spread in common age-related neurodegenerative diseases. It will be important to better understand the molecular and cellular mechanisms governing the role of these aggregating proteins in neural function, especially at synapses, how their propagation occurs and how pathogenesis is promoted by aging.
    Full-text · Article · Nov 2013 · International Journal of Cell Biology
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    • "Frontotemporal dementia (FTD), the second most common form of presenile dementia, and amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain, are regarded as closely related conditions [1]. Genetic mutations and pathological proteins associated with both diseases include valosin-containing protein [2], [3], multivesicular body protein 2B [4], [5], ubiquilin 2 [6], chromosome 9 open reading frame 72 [7], [8], transactive response DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) [9]–[13]. "
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    ABSTRACT: Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts.
    Full-text · Article · Oct 2013 · PLoS ONE
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