9 research outputs found
Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide
Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14â15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genomeâwide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits lateâstage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagyâlysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.</p
A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1Îą-SIRT3-UCP2 Axis
A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain
Initial brain aging:heterogeneity of mitochondrial size is associated with decline in complex I-linked respiration in cortex and hippocampus
Lactate Transport and Receptor Actions in Retina:Potential Roles in Retinal Function and Disease
Author Correction: Rev1 contributes to proper mitochondrial function via the PARP-NAD+-SIRT1-PGC1Îą axis
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper
Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimerâs disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinsonâs disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ1â42 and Aβ1â40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention
A high-fat diet and NAD<sup>+</sup> activate sirt1 to rescue premature aging in cockayne syndrome
SummaryCockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/m mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS