A5058571290- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Genetic Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Calcium signaling and nucleotide metabolism
- Lysosomal Storage Disorders Research
- Anesthesia and Sedative Agents
- Ubiquitin and proteasome pathways
- Intensive Care Unit Cognitive Disorders
- Mitochondrial Function and Pathology
- Toxoplasma gondii Research Studies
- Heat shock proteins research
- Muscle Physiology and Disorders
- Cardiac, Anesthesia and Surgical Outcomes
- EEG and Brain-Computer Interfaces
- Optical Imaging and Spectroscopy Techniques
- Cardiac Valve Diseases and Treatments
- Blood transfusion and management
- Blood donation and transfusion practices
- Infective Endocarditis Diagnosis and Management
- Functional Brain Connectivity Studies
- Hippo pathway signaling and YAP/TAZ
- RNA regulation and disease
- Neurological diseases and metabolism
University of Cambridge
2011-2024
University of Naples Federico II
2004-2024
Wellcome Trust
2012-2021
John Radcliffe Hospital
2020
University of Oxford
2020
Wellcome/MRC Cambridge Stem Cell Institute
2018
UK Dementia Research Institute
2018
Oxford University Hospitals NHS Trust
2018
Addenbrooke's Hospital
2009-2017
University of Salerno
1996-2009
Autophagic protein degradation is mediated by autophagosomes that fuse with lysosomes, where their contents are degraded. The membrane origins of may involve multiple sources. However, it unclear if and distinct sources during autophagosome biogenesis. Vesicles containing mATG9, the only transmembrane autophagy protein, seen in many sites, fusions other autophagic compartments have not been visualized mammalian cells. We observed mATG9 traffics from plasma to recycling endosomes carriers...
SummaryAutophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), potent cellular messenger, inhibits autophagosome synthesis via number of mechanisms. NO impairs by inhibiting the activity S-nitrosylation substrates, JNK1 IKKβ. Inhibition reduces Bcl-2 phosphorylation...
Autophagy is a catabolic process in which lysosomes degrade intracytoplasmic contents transported double-membraned autophagosomes. Autophagosomes are formed by the elongation and fusion of phagophores, can be derived from preautophagosomal structures coming plasma membrane other sites like endoplasmic reticulum mitochondria. The mechanisms elongate their membranes mature toward fully autophagosomes still remain unknown. Here, we show that maturation early Atg16L1 precursors requires...
Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients chronic inflammatory lung diseases, such as cystic fibrosis (CF), results improved outcomes. Paradoxically, recent study reported that CF associated increased infection nontuberculous mycobacteria (NTM). Here, we confirm long-term by adults the development NTM, particularly multi-drug-resistant species Mycobacterium abscessus, and identify an underlying...
Abstract Contact inhibition enables noncancerous cells to cease proliferation and growth when they contact each other. This characteristic is lost undergo malignant transformation, leading uncontrolled solid tumor formation. Here we report that autophagy compromised in contact-inhibited 2D or 3D-soft extracellular matrix cultures. In such cells, YAP/TAZ fail co-transcriptionally regulate the expression of myosin-II genes, resulting loss F-actin stress fibers, which impairs autophagosome The...
Autophagy is a critical pathway that degrades intracytoplasmic contents by engulfing them in double-membraned autophagosomes are conjugated with LC3 family members. These membranes specified phosphatidylinositol 3-phosphate (PI3P), which recruits WIPI2, which, turn, ATG16L1 to specify the sites of LC3-conjugation. Conventionally, phosphatidylinositides act concert other proteins targeting effectors specific membranes. Here we describe WIPI2 localizes autophagic precursor binding RAB11A,...
Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of polyglutamine repeat region within ataxin-3 protein. The mutant protein forms intracellular aggregates in brain. However, cellular mechanisms causing toxicity are still poorly understood and there currently no effective treatments. In this study we show that administration rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance transgenic mouse model spinocerebellar 3....
Acetoin is a major extracellular product of Bacillus subtilis grown on glucose and other fermentable carbon sources. The enzymes responsible for the formation acetoin, acetolactate synthase, decarboxylase are synthesized in detectable amounts only cells that have reached stationary phase. We cloned sequenced genes encoding these enzymes, alsS alsD, as well gene, alsR, regulates their expression. alsD appear to compose single operon, while alsR transcribed divergently from alsSD operon. AlsR...
Huntington's disease (HD) is an autosomal dominant neurodegenerative caused by a polyglutamine expansion in huntingtin. There are no treatments that known to slow the neurodegeneration this mutation. Mutant huntingtin causes via toxic gain-of-function mechanism and has propensity aggregate form intraneuronal inclusions. One therapeutic approach for HD enhance degradation of mutant protein. We have shown can be achieved upregulating autophagy, using drug rapamycin. In order find safer ways...
Many neurodegenerative diseases exhibit protein accumulation and increased oxidative stress. Therapeutic strategies include clearing aggregate-prone proteins by enhancing autophagy or decreasing stress with antioxidants. autophagy-inducing stimuli increase reactive oxygen species (ROS), raising concerns that the benefits of up-regulation may be counterbalanced ROS toxicity. Here we show not all inducers significantly ROS. However, many antioxidants inhibit both basal induced autophagy. By...
Abstract Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Mutated CCT4/5 subunits cause sensory neuropathy and CCT5 expression decreased in Alzheimer’s disease. Here, we show that integrity essential for autophagosome degradation cells or Drosophila this phenomenon orchestrated the actin cytoskeleton. When autophagic flux reduced compromise of individual subunits, disease-relevant autophagy substrates accumulate...
Autophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead accumulation misfolded proteins in neurons might be involved chronic neurodegenerative diseases. Here, we uncover an essential role for syntaxin-5 SNARE complex autophagy. Using genetic knockdown, show regulates later stages autophagy after initial formation autophagosomes. This acts on by regulating...
Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, has been considered as a potential therapeutic target. This is upstream mTORC1, negative regulator autophagy. Thus, we expected autophagy to be activated by insulin-like factor-1 (IGF-1) inhibition, which could account for many its beneficial effects. Paradoxically, found that IGF-1 inhibition attenuates autophagosome formation. The reduced...
Abstract Autophagy is an important degradation pathway, which induced after starvation, where it buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. While the classical pathway mediating this response via mTOR inhibition, there are likely be additional pathways that support process. Here, we identify Annexin A2 as autophagy modulator regulates autophagosome formation enabling appropriate ATG9A trafficking endosomes autophagosomes actin. This process...
Autophagosomes are formed by double-membraned structures, which engulf portions of cytoplasm. ultimately fuse with lysosomes, where their contents degraded. The origin the autophagosome membrane may involve different sources, such as mitochondria, Golgi, endoplasmic reticulum, plasma membrane, and recycling endosomes. We recently observed that ATG9 localizes on in clathrin-coated structures is internalized following a classical endocytic pathway through early then By contrast, ATG16L1 also...
The baseline value of the Bispectral Index (BIS) is 96–99 in awake state. Patients with Alzheimer's disease or vascular dementia may show an increase slow wave and a decrease fast activity electroencephalogram (EEG). BIS presumed to EEG slowing. We hypothesized that "awake" lower than normal elderly patients. studied 36 patients multiinfarct control aged >75 yr. Both groups were assessed Mini-Mental State Test. (version 3.4) was recorded from frontal derivation using Aspect A-2000 monitor....
Perturbations in autophagy and apoptosis are associated with cancer development. XIAP cIAP1 two members of the inhibitors protein family whose expression is elevated different cancers. Here we report that induce by upregulating transcription Beclin 1, an essential gene. The E3 ubiquitin ligase activity both proteins activates NFκB signalling, leading to direct binding p65 promoter 1 its transcriptional activation. This mechanism may be relevant cells, since found increased levels B-cell...