Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS.

Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans.

Stories of restitution: Family experiences of diagnosis and help-seeking for a child with cerebral palsy.

BACKGROUND: The experience of living with children with CP is dominated by the voice of the mother while others are rarely reported. Incorporation of the voices of other family members is important for a holistic understanding. METHODS: Drawing on the philosophical perspectives of pragmatism, generic qualitative methodology, and Frank's narratives, this article highlights how restitution was constructed by 30 family members. FINDINGS: They constructed restitution by hoping for a cure through either biomedical and/or alternative models of treatment, followed by intransitive and transcendent restitution. DISCUSSION: This appears to be the first time that restitution has been extended to families living with children with chronic illnesses. APPLICATION TO PRACTICE: This would mean that paediatric nursing professionals and other health professionals dealing with family members living with children with CP could attend to their stories in an open and focused manner to honour and validate their stories as well as their experiences.

Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose.

Chronic wasting disease (CWD) is the transmissible spongiform encephalopathy or prion disease affecting cervids. In 2016, the first cases of CWD were reported in Europe in Norwegian wild reindeer and moose. The origin and zoonotic potential of these new prion isolates remain unknown. In this study to investigate zoonotic potential we inoculated brain tissue from CWD-infected Norwegian reindeer and moose into transgenic mice overexpressing human prion protein. After prolonged postinoculation survival periods no evidence for prion transmission was seen, suggesting that the zoonotic potential of these isolates is low.

Pharmaceutical Assessment of Melia azedarach Gum as a Binder and Disintegrant in Immediate-Release Tablets.

Excipients are components other than active ingredients that are added to pharmaceutical formulations. Naturally sourced excipients are gradually gaining preeminence over synthetically sourced excipients due to local availability and continuous supply. This study aimed to investigate the binding and disintegrating characteristics of gum extracted from the bark of Melia azedarach tree. The bark of Melia azedarach was harvested from Kwahu Asasraka in Ghana. The gum was extracted with ethanol (96%), and the percentage yield, phytochemical constituents, and flow characteristics were assessed. As a disintegrant, the gum was utilized to formulate granules at varying concentrations of 5% w/w and 10% w/w using starch as the standard. The gum was also utilized to prepare granules at varying concentrations of 10% w/v and 20% w/v as a binder, with tragacanth gum serving as the reference. Eight batches of tablets were produced from the granules. The formulated tablets from each batch were then subjected to quality control testing, which included uniformity of weight, friability, disintegration, hardness, drug content, and dissolution tests, respectively. Tannins, saponins, alkaloids, and glycosides were identified in the Melia azedarach gum. The gum had a percentage yield of 67.75% and also exhibited good flow properties. All tablets passed the uniformity of weight, friability, disintegration, hardness, dissolution, and drug content tests, respectively. According to the findings of the study, Melia azedarach gum can be utilized as an excipient in place of tragacanth and starch as a binder and disintegrant, respectively, in immediate-release tablets.

Profile of suicide within the northern part of Ghana: A decade under review.

BACKGROUND: Several reports show that suicide is the second and third leading cause of untimely death in young people below the age of 30. Little, however, is known about the profile and trend of suicide in this country due to lack of systematic studies and a lack of national statistics on suicide. This study seeks to examine the profile and pattern of suicide cases recorded within northern Ghana for the past decade. AIM: This study aimed to report the prevalence of suicide as an independent cause of death; the choice of suicide method and the alleged reasons for suicide within the northern part of Ghana. SETTING: Retrospective review of coroners' reports within the northern part of Ghana. METHOD: In this descriptive study, 309 completed suicides as archived by the office of the coroner were examined. The coroners' reports of 309 individuals, whose deaths received a suicide verdict or an open verdict in which the cause of death was likely to be suicide from 2008 to 2017, were examined. Student's t-test was used to ascertain significant age differences between the genders involved. RESULTS: Amongst the 309 decedents examined, approximately, 61% were male, with ages ranging from 5 to 81 years. Hanging and poisoning were the most commonly used methods to complete suicide accounting for 124 (40.1%) and 102 (33.0%) deaths, respectively. Regarding the reasons for completed suicide, 78 (25.2%) were because of unknown reasons and 66 (21.4%) were because of social stigma. There was a notable decline in the prevalence of suicide from 2014 to 2017 compared with the years from 2010 to 2013. CONCLUSION: Suicide was highest in the 30-39 year age group with hanging and poisoning being the most common method employed. Stigmatisation and psychosocial problems arising from chronic illness and economic hardship were significant triggers of suicide amongst the suicide decedents in the northern part of Ghana.

A naturally occurring variant of the human prion protein completely prevents prion disease.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

Adipose Tissue from Lean and Obese Mice Induces a Mesenchymal to Epithelial Transition-Like Effect in Triple Negative Breast Cancers Cells Grown in 3-Dimensional Culture.

Breast cancer is the second leading cause of cancer-related mortality among women globally with obesity being one risk factor. Obese breast cancer patients have at least a 30% increased risk of death from breast cancer compared to non-obese breast cancer patients because they present with larger tumors and generally have increased rates of metastasis. Moreover, obese breast cancer patients respond more poorly to treatment compared to non-obese patients, particularly pre-menopausal women diagnosed with triple negative breast cancer (TNBC). To help understand the molecular mechanisms underlying the increased metastasis associated with obesity, we previously established a three-dimensional culture system that permits the co-culture of adipocytes and TNBC cells in a manner that mimics an in vivo milieu. Using this system, we demonstrate that white adipose tissue from both lean and obese mice can induce a partial mesenchymal-to-epithelial transition (MET). Triple negative breast cancer cells adopt an epithelial morphology and have an increased expression of some epithelial markers, but they maintain the expression of mesenchymal markers, furnishing the breast cancer cells with hybrid properties that are associated with more aggressive tumors. Thus, these data suggest that adipose tissue has the potential to promote secondary tumor formation in lean and obese women. Further work is needed to determine if targeting the partial MET induced by adipose tissue could reduce metastasis.

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP-positive humans with the emergence of new strain features.

Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS.

Inherited prion disease (IPD) is caused by autosomal-dominant pathogenic mutations in the human prion protein (PrP) gene (PRNP). A proline to leucine substitution at PrP residue 102 (P102L) is classically associated with Gerstmann-Sträussler-Scheinker (GSS) disease but shows marked clinical and neuropathological variability within kindreds that may be caused by variable propagation of distinct prion strains generated from either PrP 102L or wild type PrP. To-date the transmission properties of prions propagated in P102L patients remain ill-defined. Multiple mouse models of GSS have focused on mutating the corresponding residue of murine PrP (P101L), however murine PrP 101L, a novel PrP primary structure, may not have the repertoire of pathogenic prion conformations necessary to accurately model the human disease. Here we describe the transmission properties of prions generated in human PrP 102L expressing transgenic mice that were generated after primary challenge with ex vivo human GSS P102L or classical CJD prions. We show that distinct strains of prions were generated in these mice dependent upon source of the inoculum (either GSS P102L or CJD brain) and have designated these GSS-102L and CJD-102L prions, respectively. GSS-102L prions have transmission properties distinct from all prion strains seen in sporadic and acquired human prion disease. Significantly, GSS-102L prions appear incapable of transmitting disease to conventional mice expressing wild type mouse PrP, which contrasts strikingly with the reported transmission properties of prions generated in GSS P102L-challenged mice expressing mouse PrP 101L. We conclude that future transgenic modeling of IPDs should focus exclusively on expression of mutant human PrP, as other approaches may generate novel experimental prion strains that are unrelated to human disease.

Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.

Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals. However, some, and in particular an extensively studied type of Gerstmann-Sträussler-Scheinker syndrome (GSS) caused by a PRNP A117V mutation, are thought not to generate infectious prions and instead constitute prion proteinopathies with a quite distinct pathogenetic mechanism. Multiple attempts to transmit A117V GSS have been unsuccessful and typical protease-resistant PrP (PrP(Sc)), pathognomonic of prion disease, is not detected in brain. Pathogenesis is instead attributed to production of an aberrant topological form of PrP, C-terminal transmembrane PrP ((Ctm)PrP). Barriers to transmission of prion strains from one species to another appear to relate to structural compatibility of PrP in host and inoculum and we have therefore produced transgenic mice expressing human 117V PrP. We found that brain tissue from GSS A117V patients did transmit disease to these mice and both the neuropathological features of prion disease and presence of PrP(Sc) was demonstrated in the brains of recipient transgenic mice. This PrP(Sc) rapidly degraded during laboratory analysis, suggesting that the difficulty in its detection in patients with GSS A117V could relate to post-mortem proteolysis. We conclude that GSS A117V is indeed a prion disease although the relative contributions of (Ctm)PrP and prion propagation in neurodegeneration and their pathogenetic interaction remains to be established.

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.

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.

Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

EfficientMaize: A Lightweight Dataset for Maize Classification on Resource-Constrained Devices.

Hyperspectral imaging, combined with deep learning techniques, has been employed to classify maize. However, the implementation of these automated methods often requires substantial processing and computing resources, presenting a significant challenge for deployment on embedded devices due to high GPU power consumption. Access to Ghanaian local maize data for such classification tasks is also extremely difficult in Ghana. To address these challenges, this research aims to create a simple dataset comprising three distinct types of local maize seeds in Ghana. The goal is to facilitate the development of an efficient maize classification tool that minimizes computational costs and reduces human involvement in the process of grading seeds for marketing and production. The dataset is presented in two parts: raw images, consisting of 4,846 images, are categorized into bad and good. Specifically, 2,211 images belong to the bad class, while 2,635 belong to the good class. Augmented images consist of 28,910 images, with 13,250 representing bad data and 15,660 representing good data. All images have been validated by experts from Heritage Seeds Ghana and are freely available for use within the research community.

Microwave Thermal Ablation for Breast Cancer in Africa: A Pioneering Case Report Utilizing TATOpro.

The adoption of minimally invasive treatments for early-stage breast cancer is increasing. Microwave thermal ablation (MWA), a minimally invasive technique, has been studied for treating small breast cancer lesions. However, long-term evidence on its efficacy as a sole treatment is limited, as most studies combine MWA with other therapies and post-treatment surgical excision. This report details the case of an 83-year-old African patient who declined surgery and systemic therapies, opting for MWA using the TATOpro system as the sole treatment for contralateral breast cancer with axillary lymph node metastasis. The report includes a one-year follow-up, assessing disease recurrence with MRI and ultrasound. The findings highlight MWA's potential as an innovative and efficacious breast cancer treatment, emphasizing the need for adaptable strategies in oncology.

Exploring virtual funding committee practices in the allocation of National Institute for Health and Care Research funding: A netnographic study.

Background: Funding committees, comprising members with a range of knowledge, skills, and experience, are considered integral to the decision-making process of funding organisations for recommending or allocating research funding. However, there is limited research investigating the decision-making processes, the role of members and their social interactions during funding committee meetings conducted both virtually and face-to-face. Methods: Using a mixed-methods design and following netnography principles, the study observed nine National Institute for Health and Care Research programmes funding committee meetings conducted virtually during October 2020 to December 2021; complemented by interviews with committee chairs and members (18 interviews) and NIHR staff (12 interviews); an online survey (50 responses); and documentary analysis. Personal reflections through immersive journals also formed part of the analysis. Results: Three main themes were identified from the observations, interviews, and online survey: efficiency of virtual committee meetings (importance of preparation, and the role of formality, process, and structure); understanding the effect of virtual committee meetings on well-being (effects of fatigue and apprehension, and the importance of work life balance); understanding social interactions and engagement (levels of engagement, contribution and inclusivity, awareness of unconscious bias and the value of social networking). Conclusions: Examining the decision-making practices of one funding organisation across several research programmes, across multiple committee meetings over one year has generated new insights around funding committee practices that previous studies have not been able to explore or investigate. Overall, it was observed that fair and transparent funding recommendations and outcomes can be achieved through virtual funding committees. However, whilst virtual funding committees have many benefits and opportunities, such as the potential to increase membership diversity and inclusivity, and be more environmentally sustainable, more evidence is needed to evaluate their effectiveness, with particular focus on issues of fatigue, engagement, and committee cohesion, especially when new committee members join.

Analysis, treatment modality and demographic characteristics of urolithiasis patients visiting Korle-Bu Teaching Hospital in Ghana.

Background: Globally urolithiasis is on the rise and gradually becoming a public health concern due to the associated complications. This study reviewed the demographic characteristics, the chemical composition of stones, treatment modality and duration of hospitalisation of urolithiasis patients at Korle-Bu Teaching Hospital, Accra, Ghana. Materials and Methods: This was a retrospective study conducted between March 2019 and April 2022. Data from consecutive patients treated for urolithiasis were used for this study. Data on demographic characteristics, stones chemical composition, urine factors, urolithiasis treatment modality and duration of hospital stay after therapy were collated and analysed using descriptive and inferential approaches. Results: The age of the patients ranged from 2 to 75 years with a mean of 45 (±13.4). The predominant age group for stone formation was 30-39 years - 52(26.3%). Urolithiasis was common among patients in the formal employment sector: 81(40.9%). All stones had two or more chemical compositions, with the combination of calcium oxalate monohydrate, calcium oxalate dihydrate and uric acid being the predominant stone type: 88(57.5%). Ureteroscopy with semi-rigid and Percutaneous nephrolithotomy were the predominant treatment modalities: 105(53.0%) and 74(37.4%), respectively. Escherichia coli was responsible for most urinary tract infections in urolithiasis patients 8(4.0%) and the least duration of hospital stay after the procedure was associated with the use of semi-rigid ureteroscope as the treatment modality with a median duration of 2 days (1-2 days) with P < 0.0001. Conclusions: Urolithiasis was predominant among professionals in the formal sector. All stones were mixed with Calcium oxalate monohydrate, calcium oxalate dihydrate, and uric acid combination being the majority. Ureteroscopy with semi-rigid and percutaneous nephrolithotomy were the common treatment modality.

Advancing Prostate Cancer Staging: A Single-Step Approach With Bi-parametric and Whole-Body Diffusion MRI in an African Cohort.

OBJECTIVES:  To document our initial experience using whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) and bi-parametric magnetic resonance imaging (bpMRI) as a single exam in the staging of biopsy-proven prostate cancers. METHODS: This retrospective study involved 120 African men with biopsy-confirmed prostate cancer (PCa). All the participants had a single exam that included both a bpMRI and a WB-DWI/MRI. The results were analyzed based on the American Urological Association's risk stratification system and evaluated using descriptive statistics. RESULTS: The combined imaging approach confirmed PCa in all cases, identifying pelvic lymph node metastases in 21 (17.5%) patients. Among 72 high-risk patients, bpMRI+WB-DWI/MRI detected pelvic lymph node metastases in 18 (25.0%), bone metastases in 15 (20.8%), retroperitoneal lymph node metastases in six (8.3%), and extraprostatic extension in 18 (25%), with no solid organ metastases observed. CONCLUSION: The combination of WB-DWI/MRI and bpMRI in a single-step approach demonstrates diagnostic potential in primary prostate cancer staging for high-risk groups, with the added advantage of shorter examination times, lower patients' costs, and elimination of the risks of adverse events associated with the use of contrast agents and exposure to radiation.

Atypical scrapie prions from sheep and lack of disease in transgenic mice overexpressing human prion protein.

Public and animal health controls to limit human exposure to animal prions are focused on bovine spongiform encephalopathy (BSE), but other prion strains in ruminants may also have zoonotic potential. One example is atypical/Nor98 scrapie, which evaded statutory diagnostic methods worldwide until the early 2000s. To investigate whether sheep infected with scrapie prions could be another source of infection, we inoculated transgenic mice that overexpressed human prion protein with brain tissue from sheep with natural field cases of classical and atypical scrapie, sheep with experimental BSE, and cattle with BSE. We found that these mice were susceptible to BSE prions, but disease did not develop after prolonged postinoculation periods when mice were inoculated with classical or atypical scrapie prions. These data are consistent with the conclusion that prion disease is less likely to develop in humans after exposure to naturally occurring prions of sheep than after exposure to epizootic BSE prions of ruminants.

Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice.

Mutations in the charged multivesicular body protein 2B (CHMP2B) gene cause frontotemporal lobar degeneration. The mutations lead to C-terminal truncation of the CHMP2B protein. We generated Chmp2b knockout mice and transgenic mice expressing either wild-type or C-terminally truncated mutant CHMP2B. The transgenic CHMP2B mutant mice have decreased survival and show progressive neurodegenerative changes including gliosis and increasing accumulation of p62- and ubiquitin-positive inclusions. The inclusions are negative for the TAR DNA binding protein 43 and fused in sarcoma proteins, mimicking the inclusions observed in patients with CHMP2B mutation. Mice transgenic for mutant CHMP2B also develop an early and progressive axonopathy characterized by numerous amyloid precursor protein-positive axonal swellings, implicating altered axonal function in disease pathogenesis. These findings were not observed in Chmp2b knockout mice or in transgenic mice expressing wild-type CHMP2B, indicating that CHMP2B mutations induce degenerative changes through a gain of function mechanism. These data describe the first mouse model of dementia caused by CHMP2B mutation and provide new insights into the mechanisms of CHMP2B-induced neurodegeneration.