Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide

Background:Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer’s disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ42) that deposits in the Alzheimer’s disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45–49 residues in length. Objective:We aimed to test neurotoxicity of Aβ42 vis-á-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. Methods:We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ42. These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results:The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ42 was produced. Conclusion:These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ42

Recent advances in cutaneous lymphoma—implications for current and future classifications

The Revised European-American Classification of mature lymphoid neoplasms published in 1994 and the 2001, 2008 and 2016 WHO classifications that followed, were the product of international collaboration and consensus amongst haematopathologists, geneticists, molecular scientists and clinicians. Primary cutaneous lymphomas were fully incorporated into this process following the publication of the WHO-EORTC classification of cutaneous lymphomas in 2005. The definition, diagnostic criteria and recommended studies for primary cutaneous lymphoma continue to be refined. The 2022 International Consensus Classification represents the most recent update and an overview of all the main entities presenting primarily in the skin, together with the major changes in classification, are summarized herein. Primary cutaneous marginal zone lymphoma is segregated from other extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma) and downgraded to a lymphoproliferative disorder in line with its markedly indolent behaviour. In addition, two subtypes are recognised, based largely but not exclusively on whether they are heavy chain class-switched or IgM positive. Similarly, in keeping with a trend to greater conservatism, primary cutaneous acral CD8 positive T cell lymphoma is now also classified as a lymphoproliferative disorder. In addition, significant new insights into the biology of primary cutaneous lymphoma have also recently been forthcoming and will be presented. These studies have enhanced our knowledge of genetic, epigenetic and transcriptional changes in this group of diseases. They not only identify potential targets for novel therapies, but also raise as yet unanswered questions as to how we categorise cutaneous lymphomas, particularly with respect to relationships with similar lymphomas at extracutaneous sites

Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease

AbstractThe dopaminergic neurotoxin N-methyl,4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) causes a syndrome in primates and humans which mimics Parkinson's disease (PD) in clinical, pathological, and biochemical findings, including diminished activity of complex I in the mitochondrial electron transport chain. Reduced complex I activity is found in sporadic PD and can be transferred through mitochondrial DNA, suggesting a mitochondrial genetic etiology. We now show that MPTP treatment of mice and N-methylpyridinium (MPP+) exposure of human SH-SY5Y neuroblastoma cells increases oxygen free radical production and antioxidant enzyme activities. Cybrid cells created by transfer of PD mitochondria exhibit similar characteristics; however, PD cybrids' antioxidant enzyme activities are not further increased by MPP+ exposure, as are the activities in control cybrids. PD mitochondrial cybrids are subject to metabolic and oxidative stresses similar to MPTP parkinsonism and provide a model to determine mechanisms of oxidative damage and cell death in PD

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4

BackgroundAccumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer’s disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.MethodsWe used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.ResultsWe show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer’s Disease mice model. The same results are seen in a human in vitro model of AD.ConclusionTogether, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt

Underground tales, overground lives: mobile work identities through to post-retirement

Although there has been recent attention given to the subject of mobile work, there has been less focus, within mobility studies, on the work of those who enable movement: the job of the transport worker. This article takes this incarnation of mobile workers as the basis for understanding the ways in which mobile work identities are pulled through into retirement. The article firstly proposes that transport workers, as movement enablers, have particular identities, and are an important and neglected topic of study within mobilities. Secondly, it suggests that the post-work identities of mobile workers are contingent on their experiences during their working lives and that these are particular to mobile work. The article is evidenced through data gathered during a mobile ethnographic study with two retired London Underground employees. The participants joined the researchers on a walking tour of a disused underground railway station in London, ‘Hidden London’, organised by the London Transport Museum and their experiences and emotional responses were recorded and analysed. Understanding post-work identities through the embodied and spatial experiences of the present, the research sought insights of the past and future; the continuity and fluidity of working identities that permeated through to post-work lives. This article argues that mobile work identities are specific identities that shape a distinct post-retirement identity

Effect of atorvastatin on glycaemia progression in patients with diabetes:an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS)

AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. METHODS: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA(1c) data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA(1c) of ≥0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA(1c) as a continuous endpoint. RESULTS: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA(1c) was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA(1c) predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA(1c) change (interaction p value 0.229). CONCLUSIONS/INTERPRETATION: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3802-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users