Andrey Y Abramov

University College London | UCL · Institute of Neurology

Programmed cell death (apoptosis) is essential part of the process of tissue regeneration that also plays role in the mechanism of pathology. The phenomenon of fast and transient permeability of mitochondrial membranes by various triggers, known as permeability transition pore (mPTP) leads to the release of proapoptotic proteins and acts as an init...

Despite recent technological progress, carbon monoxide poisoning is still one of the leading causes of domestic and industrial morbidity and mortality. The brain is particularly vulnerable to CO toxicity, and thus the majority of survivors develop delayed movement and cognitive complications. CO binds to haemoglobin in erythrocytes, preventing oxyg...

Intracellular communication and regulation in brain cells is controlled by the ubiquitous Ca2+ and by redox signalling. Both of these independent signalling systems regulate most of the processes in cells including the cell surviving mechanism or cell death. In physiology Ca2+ can regulate and trigger reactive oxygen species (ROS) production by var...

The interplay between Ca 2+ ions and neuronal dysfunction has recently gained significant attention. A growing body of evidence implicates Ca 2+ in the pathophysiology of neurodegenerative disorders, including Parkinson's disease. The rate of protein aggregate formation, mitophagy, and autophagy abnormalities in Parkinson's disease may be influence...

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neu...

Alteration of mitochondrial metabolism by various mutations or toxins leads to various neurological conditions. Age-related changes in energy metabolism could also play the role of a trigger for neurodegenerative disorders. Nonetheless, it is not clear if restoration of ATP production or supplementation of brain cells with substrates for energy pro...

Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated s...

Heat shock protein 70 (HSP70) is activated under stress response. Its involvement in cell protection, including energy metabolism and quality control makes it a promising pharmacological target. A strategy to increase HSP70 levels inside the cells is the application of recombinant HSP70. However, cell permeability and functionality of these exogeno...

The transmembrane receptor for advanced glycation end products (RAGE) is a signaling receptor for many damage‐ and pathogen‐associated molecules. Activation of RAGE is associated with inflammation and an increase in reactive oxygen species (ROS) production. Although several sources of ROS have been previously suggested, how RAGE induces ROS product...

Profound changes in the metabolism of cancer cells have been known for almost 100 years, and many aspects of these changes have continued to be actively studied and discussed. Differences in the results of various studies can be explained by the diversity of tumours, which have differing processes of energy metabolism, and by limitations in the met...

During hypoxia, increases in cerebral blood flow maintain brain oxygen delivery. Here, we describe a mechanism of brain oxygen sensing that mediates the dilation of intraparenchymal cerebral blood vessels in response to reductions in oxygen supply. In vitro and in vivo experiments conducted in rodent models show that during hypoxia, cortical astroc...

Flavin adenine dinucleotide (FAD) autofluorescence from cells reports on the enzymatic activity which involves FAD as a cofactor. Most of the cellular FAD fluorescence comes from complex II of the electron transport chain in mitochondria and can be assessed with inhibitor analysis. The intensity of FAD autofluorescence is not homogeneous and vary b...

The aim of this work was to study the regulation of insulin production by synucleins. In addition, we aimed to evaluate the possible efect of 1267 nm light irradiation, which leads to singlet oxygen production, on insulin production in the animal organism. the present work showed that knockout of genes encoding synuclein proteins is associated with...

The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of...

Alterations in function of hypoxanthine guanine phosphoribosyl transferase (HPRT), one of the major enzymes involved in purine nucleotide exchange, lead to overproduction of uric acid and produce various symptoms of Lesch-Nyhan syndrome (LNS). One of the hallmarks of LNS is maximal expression of HPRT in the central nervous system with the highest a...

Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), w...

Mutations in the SNCA gene cause autosomal dominant Parkinsons disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of alpha-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising huma...

Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we...

All forms of dementia including Alzheimer’s disease are currently incurable. Mitochondrial dysfunction and calcium alterations are shown to be involved in the mechanism of neurodegeneration in Alzheimer’s disease. Previously we have described the ability of compound Tg-2112x to protect neurons via sequestration of mitochondrial calcium uptake and w...

Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeos...

Singlet oxygen (1O2) is an electronically excited state of triplet oxygen which is less stable than molecular oxygen in the electronic ground state and produced by photochemical, thermal, chemical, or enzymatic activation of O2. Although the role of singlet oxygen in biology and medicine was intensively studied with photosensitisers, using of these...

Inorganic polyphosphate is a polymer which plays multiple important roles in yeast and bacteria. In higher organisms the role of polyP has been intensively studied in last decades and involvements of this polymer in signal transduction, cell death mechanisms, energy production, and many other processes were demonstrated. In contrast to yeast and ba...

Aggregation of α-Synuclein (α-Syn) drives Parkinson's disease, although the initial stages of self-assembly and structural conversion have not been captured inside neurons. We track the intracellular conformational states of α-Syn utilizing a single-molecule FRET biosensor, and show that α-Syn converts from its monomeric state to form two distinct...

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is induced by the loss ofdopaminergic neurons in the midbrain. The mechanism of neurodegeneration is associated with the aggregation of misfolded proteins, oxidative stress, and mitochondrial dysfunction. Considering this the process of removal ofdamaged organelles or protein...

Background & Aims: In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute...

In low oxygen conditions, increases in cerebral blood flow maintain brain oxygen delivery but the mechanisms underlying hypoxia-induced dilations of cerebral vasculature are incompletely understood. Here we show that astrocytes accumulate nitrite and in response to hypoxia produce nitric oxide via mitochondrial reduction of nitrite by a molybdenum-...

Neurodegenerative disorders are currently incurable devastating diseases which are characterized by the slow and progressive loss of neurons in specific brain regions. Progress in the investigation of the mechanisms of these disorders helped to identify a number of genes associated with familial forms of these diseases and a number of toxins and ri...

To overcome oxidative, inflammatory, and metabolic stress, cells have evolved cytoprotective protein networks controlled by nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its negative regulator, Kelch-like ECH associated protein 1 (Keap1). Here, using high-resolution mass-spectrometry we characterize the proteomes of macrophages with al...

Болезнь Паркинсона (БП) представляет собой прогрессирующее нейродегенеративное заболевание, вызванное потерей дофаминергических нейронов среднего мозга. Механизм нейродегенерации связан с накоплением патологических белковых агрегатов, окислительным стрессом и митохондриальной дисфункцией. В ряде исследований показано, что в развитие нейродегенераци...

This work presents results of in vivo and in situ measurements of hepatocellular carcinoma by a developed optical biopsy system. Here, we describe the technical details of the implementation of fluorescence lifetime and diffuse reflectance measurements by the system, equipped with an original needle optical probe, compatible with the 17.5G biopsy n...

Intracellular quality control regulated by autophagy process is important for maintenance of cellular homeostasis. Deregulation of autophagy and more specifically mitophagy leads to accumulation of the misfolded proteins and damaged mitochondria that in turn leads to the cell loss. Alteration of autophagy and mitophagy has shown to be involved in t...

Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age-related changes in mitochondrial metabolism....

Parkinson's disease (PD) is a progressive neurodegenerative disorder induced by the loss of dopaminergic neurons in midbrain. The mechanism of neurodegeneration is associated with aggregation of misfolded proteins, oxidative stress, and mitochondrial dysfunction. Considering this, the process of removal of unwanted organelles or proteins by autopha...

Regular exercise has many health benefits, among which is a significant reduction of cardiovascular risk. Although many beneficial effects of exercise are well described, the exact mechanisms by which exercise confers cardiovascular benefits are yet to be fully understood. In the current study, we have used high resolution mass spectrometry to dete...

To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator the Kelch-like ECH associated protein 1 (Keap1). Here, we used high-resolution mass-spectrometry to characterize the proteomes of macro...

Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased spl...

The brain produces various reactive oxygen species in enzymatic and non-enzymatic reactions as a by-product of metabolism and/or for redox signaling. Effective antioxidant system in the brain cells maintains redox balance. However, neurons and glia from some brain regions are more vulnerable to oxidative stress in ischemia/reperfusion, epilepsy, an...

Brain is one of the most energy-demanding organs. Energy in the form of ATP is produced in brain cells predominantly in oxidative phosphorylation coupled to mitochondrial respiration. Any alteration of the mitochondrial metabolism or prolonged ischemic or anoxic conditions can lead to serious neurological conditions, including neurodegenerative dis...

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson’s disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to...

Brain is one of the most energy-demanding organs. Energy in the form of ATP is produced in brain cells predominantly in oxidative phosphorylation coupled to mitochondrial respiration. Any alteration of the mitochondrial metabolism or prolonged ischemic or anoxic conditions can lead to serious neurological conditions, including neurodegenerative dis...

Introduction: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. Methods: Live imaging, electrophysiology, and r...

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca²⁺-independent phospholipase A2β (iPLA2...

Production of reactive oxygen species (ROS) in the mitochondria plays multiple roles in physiology, and excessive production of ROS leads to the development of various pathologies. ROS in the mitochondria are generated by various enzymes, mainly in the electron transporvt chain, and it is important to identify not only the trigger but also the sour...

Brain is not homogenous and neurons from various brain regions are known to have different vulnerabilities to mitochondrial mutations and mitochondrial toxins. However, it is not clear if this vulnerability is connected to different energy metabolism in specific brain regions. Here, using live‐cell imaging, we compared mitochondrial membrane potent...

Oxygen, in form of reactive oxygen species (ROS), has been shown to participate in oxidative stress, one of the major triggers for pathology, but also is a main contributor to physiological processes. Recently, it was found that 1267nm irradiation can produce singlet oxygen without photosensitizers. We used this phenomenon to study the effect of la...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer's disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis ind...

The development of human induced pluripotent stem cells (hiPSC) has greatly aided our ability to model neurodegenerative diseases. However, generation of midbrain dopaminergic (mDA) neurons is a major challenge and protocols are variable. Here, we developed a method to differentiate hiPSCs into enriched populations (>80%) of mDA neurons using only...

The world's population aging progression renders age‐related neurodegenerative diseases to be one of the biggest unsolved problems of modern society. Despite the progress in studying the development of pathology, finding ways for modifying neurodegenerative disorders remains a high priority. One common feature of neurodegenerative diseases is mitoc...

In Alzheimer’s disease (AD) amyloid-β (Aβ) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood–cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy sub...

Most neurodegenerative disorders are associated with aggregation and accumulation of misfolded proteins. One of these proteins, tau, is involved in a number of pathologies including Alzheimer's disease and frontotemporal dementia. Aggregation and phosphorylation of tau have been shown to be a trigger for abnormal signal transduction and disruption...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational stru...

Robust cellular models are key in determining pathological mechanisms that lead to neurotoxicity in Huntington's disease (HD) and for high throughput pre‐clinical screening of potential therapeutic compounds. Such models exist but mostly comprise non‐human or non‐neuronal cells that may not recapitulate the correct biochemical milieu involved in pa...

Inorganic polyphosphate (polyP) is a polymer present in all living organisms. Although polyP is found to be involved in a variety of functions in cells of higher organisms, the enzyme responsible for polyP production and consumption has not yet been identified. Here we studied the effect of polyP on mitochondrial respiration, oxidative phosphorylat...

Aggregation or phosphorylation of the microtubule-associated protein tau is the pathological hallmark in a number of diseases termed tauopathies, which include the most common neurodegenerative disorder, Alzheimer's disease; or frontotemporal dementia, linked to mutations in the gene MAPT encoding tau. Although misfolded tau has strong familial and...

Mitochondria control vitally important functions in cells, including energy production, cell signalling and regulation of cell death. Considering this, any alteration in mitochondrial metabolism would lead to cellular dysfunction and the development of a disease. A large proportion of disorders associated with mitochondria are induced by mutations...

Background: Skeletal muscle cells continuously generate reactive oxygen species (ROS). Excessive ROS can affect lipids resulting in lipid peroxidation (LPO). Here we investigated the effects of myotube intracellular calcium-induced signaling eliciting contractions on the LPO induction and the impact of LPO-product 4-hydroxynonenal (4-HNE) on physi...

There has been growing evidence for a critical role of oxidative stress in neurodegenerative disease, providing novel targets for disease modifying treatments. Although antioxidants have been suggested and tried in the treatment of epilepsy, it is only recently that the pivotal role of oxidative stress in the pathophysiology of status epilepticus h...

Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here,...

DJ-1 protein has multiple specific mechanisms to protect dopaminergic neurons against neurodegeneration in Parkinson's disease. Wild type DJ-1 can acts as oxidative stress sensor and as an antioxidant. DJ-1 exhibits the properties of molecular chaperone, protease, glyoxalase, transcriptional regulator that protects mitochondria from oxidative stres...

Glutamate is one of the most important neurotransmitters in the process of signal transduction in the central nervous system. Excessive amounts of this neurotransmitter lead to glutamate excitotoxicity which is accountable for neuronal death in acute neurological disorders including stroke, trauma, and in neurodegenerative diseases. Inorganic polyp...

Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs...