Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.
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ABSTRACT:
SUBMITTER: Clayton EL
PROVIDER: S-EPMC5409096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD.
| S-EPMC4575387 | biostudies-literature
Project description:Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology in neurons. We here report that physiological levels of mutant CHMP2B causes reduced numbers and significantly impaired trafficking of endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due to the stable incorporation of mutant CHMP2B onto neuronal endolysosomes, which we show renders them unable to traffic within dendrites. This defect is due to the inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for release of CHMP2B from endosomal membranes. Strikingly, both impaired trafficking and the increased dendritic branching were rescued by treatment with antisense oligonucleotides targeting the well validated frontotemporal dementia risk factor TMEM106B, which encodes an endolysosomal protein. This indicates that reducing TMEM106B levels can restore endosomal health in frontotemporal dementia. As TMEM106B is a risk factor for frontotemporal dementia caused by both C9orf72 and progranulin mutations, and antisense oligonucleotides are showing promise as therapeutics for neurodegenerative diseases, our data suggests a potential new strategy for treating the wide range of frontotemporal dementias associated with endolysosomal dysfunction.
| S-EPMC6262218 | biostudies-literature
Project description:In order to obtain an overview of gene expression changes in CHMP2B-dependent frontotemporal dementia (FTD3), RNA sequencing analyses were performed in FTD3 patient neurons compared to their gene-corrected isogenic controls.
2017-06-12 | GSE92340 | GEO
Project description:The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs) were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.
| S-EPMC5355623 | biostudies-literature
Project description:OBJECTIVE:Mutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype-phenotype associations. METHODS:All 16 exons of the OPTN gene in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin were sequenced by targeted next generation sequencing. RESULTS:Two known heterozygous missense mutations in the OPTN, c.1481T> G (p.L494W), and c.1546G> C (p.E516Q), as well as one novel heterozygous missense mutation c.1690G> C (p.D564H) were each detected in one sporadic ALS patient. The patient carrying the p.E516Q mutation developed clinical features of ALS-frontotemporal dementia (FTD) and the patient carrying the p.D564H mutation showed a phenotype of ALS. They both had an aggressive course, with a survival of 18 and 14 months respectively. Literature review showed that the clinical phenotypes in OPTN mutated ALS were not homogeneous, although some individuals showed a relatively slow progression and a long duration, some mutations carriers developed an aggressive progression and a short survival. INTERPRETATION:OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts. Mutations in optineurin can cause aggressive ALS+/-FTD.
| S-EPMC6917321 | biostudies-literature
Project description:BackgroundBehavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms.MethodsParticipants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls.Results76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups.ConclusionsLanguage deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
| S-EPMC10025186 | biostudies-literature
Project description:IntroductionBehavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present.MethodsWe assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI-R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non-mutation carriers (controls). All mutation carriers were stratified according to their global CDR plus NACC FTLD score into three groups: asymptomatic (CDR = 0), prodromal (CDR = 0.5) and symptomatic (CDR = 1+). Mixed-effects models adjusted for age, education, sex and family clustering were used to compare between the groups. Neuroanatomical correlates of the individual domains were assessed within each genetic group.ResultsCBI-R total scores were significantly higher in all CDR 1+ mutation carrier groups compared with controls [C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)] as well as their respective CDR 0.5 groups [C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)] and CDR 0 groups [C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)]. The C9orf72 and GRN 0.5 groups scored significantly higher than the controls. The greatest impairment was seen in the Motivation domain for the C9orf72 and GRN symptomatic groups, whilst in the symptomatic MAPTgroup, the highest-scoring domains were Stereotypic and Motor Behaviours and Memory and Orientation. Neural correlates of each CBI-R domain largely overlapped across the different mutation carrier groups.ConclusionsThe CBI-R detects early behavioural change in genetic FTD, suggesting that it could be a useful measure within future clinical trials.
| S-EPMC9082390 | biostudies-literature
Project description:Mutations in CHMP2B cause frontotemporal dementia (FTD) in a large Danish pedigree, which is termed FTD linked to chromosome 3 (FTD-3), and also in an unrelated familial FTD patient. CHMP2B is a component of the ESCRT-III complex, which is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. We report a novel endosomal pathology in CHMP2B mutation-positive patient brains and also identify and characterize abnormal endosomes in patient fibroblasts. Functional studies demonstrate a specific disruption of endosome-lysosome fusion but not protein sorting by the MVB. We provide evidence for a mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins necessary for fusion to occur, such as Rab7. The fusion of endosomes with lysosomes is required for neuronal function and the data presented therefore suggest a pathogenic mechanism for FTD caused by CHMP2B mutations.
| S-EPMC2865375 | biostudies-literature
Project description:A rare cause of inherited frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 leading to the autosomal dominantly inherited FTD (CHMP2B-FTD). Since CHMP2B-FTD is clinically well-characterized, and patients show a distinct pattern of executive dysfunction, the condition offers possible insight in the early electroencephalographic (EEG) changes in the cortical networks. Specifically, EEG microstate analysis parses the EEG signals into topographies believed to represent discrete network activations. We investigated the EEG dynamics in patients with symptomatic CHMP2B-FTD (n = 5) as well as pre-symptomatic mutation carriers (n = 5) compared to non-carrier family members (n = 6). The data was parsed into four archetypal microstates and global power was calculated. A trend was found for lower occurrence in microstate D in CHMP2B-FTD (p-value = 0.177, F-value = 2.036). Patients with recent symptom onset (<1 year) showed an increased duration of microstate D, whereas patients who had been symptomatic for longer periods (>2 years) showed decreased duration. Patients with CHMP2B-FTD present with executive dysfunction, and microstate D has previously been shown to be associated with the fronto-parietal network. The biphasic pattern may represent the pathophysiological changes in brain dynamics during neurodegeneration, which may apply to other neurodegenerative diseases.
| S-EPMC8475188 | biostudies-literature
Project description:The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2B(intron5) and CHMP2B(Delta10) in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2B(Delta10) induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.
| S-EPMC3013364 | biostudies-literature