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The potential for maternal nanoparticle (NP) exposures to cause developmental toxicity in the fetus without the direct passage of NPs has previously been shown, but the mechanism remained elusive. We now demonstrate that exposure of cobalt and chromium NPs to BeWo cell barriers, an in vitro model of the human placenta, triggers impairment of the autophagic flux and release of interleukin-6. This contributes to the altered differentiation of human neural progenitor cells and DNA damage in the derived neurons and astrocytes. Crucially, neuronal DNA damage is mediated by astrocytes. Inhibiting the autophagic degradation in the BeWo barrier by overexpression of the dominant-negative human ATG4BC74A significantly reduces the levels of DNA damage in astrocytes. In vivo, indirect NP toxicity in mice results in neurodevelopmental abnormalities with reactive astrogliosis and increased DNA damage in the fetal hippocampus. Our results demonstrate the potential importance of autophagy to elicit NP toxicity and the risk of indirect developmental neurotoxicity after maternal NP exposure.

Progressive mitochondrial dysfunction contributes to neuronal degeneration in age-mediated disease. An essential regulator of mitochondrial function is the deacetylase, sirtuin 3 (SIRT3). Here we investigate a role for CNS Sirt3 in mitochondrial responses to reactive oxygen species (ROS)- and Alzheimer's disease (AD)-mediated stress. Pharmacological augmentation of mitochondrial ROS increases Sirt3 expression in primary hippocampal culture with SIRT3 over-expression being neuroprotective. Furthermore, Sirt3 expression mirrors spatiotemporal deposition of β-amyloid in an AD mouse model and is also upregulated in AD patient temporal neocortex. Thus, our data suggest a role for SIRT3 in mechanisms sensing and tackling ROS- and AD-mediated mitochondrial stress.

LMX1B, a LIM-homeodomain family transcription factor, plays critical roles in the development of multiple tissues, including limbs, eyes, kidneys, brain, and spinal cord. Mutations in the human LMX1B gene cause the rare autosomal-dominant disorder Nail-patella syndrome, which affects development of limbs, eyes, brain, and kidneys. In zebrafish, lmx1b has two paralogues: lmx1ba and lmx1bb. While lmx1b morpholino data exists, stable mutants were previously lacking. Here, we describe the characterisation of lmx1b stable mutant lines, with a focus on development of tissues that are affected in Nail-patella syndrome. We demonstrate that the lmx1b paralogues have divergent developmental roles in zebrafish, with lmx1ba affecting skeletal and neuronal development, and lmx1bb affecting renal development. The double mutant, representing loss of both paralogues (lmx1b dKO) showed a stronger phenotype, which included additional defects to trunk muscle patterning, and a failure to fully inflate the notochord leading to a dramatic reduction in body length. Overall, these mutant lines demonstrate the utility of zebrafish for modelling Nail-patella syndrome and describe a previously undescribed role for lmx1b in notochord cell inflation.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson’s is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson’s. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson’s.

Human induced pluripotent stem cells (hiPSCs) are invaluable tools for research into the causes of diverse human diseases, and have enormous potential in the emerging field of regenerative medicine. Our ability to reprogramme patient cells to become hiPSCs, and to subsequently direct their differentiation towards those classes of neurons that are vulnerable to stress, is revealing how genetic mutations cause changes at the molecular level that drive the complex pathogeneses of human neurodegenerative diseases. Autophagy dysregulation is considered to be a major contributor in neural decline during the onset and progression of many human neurodegenerative diseases, meaning that a better understanding of the control of non-selective and selective autophagy pathways (including mitophagy) in disease-affected classes of neurons is needed. To achieve this, it is essential that the methodologies commonly used to study autophagy regulation under basal and stressed conditions in standard cell-line models are accurately applied when using hiPSC-derived neuronal cultures. Here, we discuss the roles and control of autophagy in human stem cells, and how autophagy contributes to neural differentiation in vitro. We also describe how autophagy-monitoring tools can be applied to hiPSC-derived neurons for the study of human neurodegenerative disease in vitro.

Aims: Tay–Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay–Sachs and Sandhoff diseases. Results: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. Innovation: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. Conclusions: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.

The Wnt/β‐catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/β‐catenin signalling pathway as a negative regulator of both basal and stress‐induced autophagy. Manipulation of β‐catenin expression levels in vitro and in vivo revealed that β‐catenin suppresses autophagosome formation and directly represses p62/SQSTM1 (encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation β‐catenin is selectively degraded via the formation of a β‐catenin–LC3 complex, attenuating β‐catenin/TCF‐driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the β‐catenin–LC3 complex is mediated by a W/YXXI/L motif and LC3‐interacting region (LIR) in β‐catenin, which is required for interaction with LC3 and non‐proteasomal degradation of β‐catenin. Thus, Wnt/β‐catenin represses autophagy and p62 expression, while β‐catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place β‐catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy. This paper describes a novel and direct interplay of beta‐catenin with crucial regulators of autophagy, establishing Wnt/β‐catenin signals as central hub in the coordination of cellular proliferation and autophagy.

In the last twenty years, research using zebrafish as a model organism has increased immensely. With the many advantages that zebrafish offer such as high fecundity, optical transparency, ex vivo development, and genetic tractability, they are well suited to studying developmental processes and the effect of genetic mutations. More recently, zebrafish models have been used to study autophagy. This important protein degradation pathway is needed for cell and tissue homeostasis in a variety of contexts. Correspondingly, its dysregulation has been implicated in multiple diseases including skeletal disorders. In this review, we explore how zebrafish are being used to study autophagy in the context of skeletal development and disease, and the ways these areas are intersecting to help identify potential therapeutic targets for skeletal disorders.

Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis.

Together, the 4 original research papers and 4 review papers convey important new insights into (i) novel mechanisms of signal control of autophagy by hypoxia, ataxia telangiectasia mutated protein kinase (ATM), the ER stress sensor inositol-requiring enzyme 1 (IRE1), and the process of O-GlcNAcylation; (ii) the role of autophagy in various age-related diseases such as cardiac fibrosis, heart failure, Parkinson’s disease, intervertebral disc degeneration (IVDD), and age-related macular degeneration (AMD); and (iii) the role of autophagy in cancer, with a particular focus on resistance mechanisms to anticancer therapy and biomarkers of chaperone-mediated autophagy (Figure 1). [figure omitted; refer to PDF] ATM is best known as a mediator of DNA damage-induced signaling. [...]they review potential neuroprotective strategies for therapeutic interventions and provide an overview of such neuroprotective mechanisms. In summary, this annual special issue has disseminated important novel developments in the field of autophagy and oxidative stress research and provides more understanding of molecular and cellular mechanisms of different diseases with emphasis on translation of knowledge to treatment, including topics of autophagy regulation and oxidative stress in aging, age-related diseases, neurodegenerative diseases, and cancer.