Kambiz Alavian

Imperial College London | Imperial · Department of Brain Sciences

Accepted features of neurodegenerative disease include mitochondrial and protein folding dysfunction and activation of pro-death factors. Neurons that experience high metabolic demand or those found in organisms with genetic mutations in proteins that control cell stress may be more susceptible to aging and neurodegenerative disease. In neurons, ev...

Significance Stressful cellular events cause intracellular Ca ²⁺ dysregulation, rapid loss of inner mitochondrial membrane potential [the permeability transition (PT)], metabolic dysfunction, and death. Rapid Ca ²⁺ -induced uncoupling is one of the most important regulators of cell demise. We show that the c-subunit ring of the F 1 F O ATP synthase...

Following exocytosis, the rate of recovery of neurotransmitter release is determined by vesicle retrieval from the plasma membrane and by recruitment of vesicles from reserve pools within the synapse, which is dependent on mitochondrial ATP. The anti-apoptotic Bcl-2 family protein Bcl-xL also regulates neurotransmitter release and recovery in part...

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhib...

An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1a (Hif-1a) in Xenopus. Hypoxia or decoupling ATP production from...

Parkinson's disease (PD) is the second most common neurodegenerative condition. Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leads to cardinal motor manifestations of the disease. Structural and physiological properties of these neurons may underlie their selective vulnerability. Among these properties, calcium dysregul...

Objective: Magnetic resonance-guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population re...

Threshold concepts are recent, yet already established, aspects of medical education. However, they represent a new area in neuroscience education, especially given the recency of neuroscience as a field of research in its own right when compared to more established STEM disciplines. In this article, we reviewed the existing literature on threshold...

Midbrain dopaminergic neurons are responsible for several functions in the reward system, control of emotion, motivation, cognition, and motor behavior. A set of well-characterized transcription factors involved in specification, neurogenesis, and neuronal differentiation determines the fate of these neurons and modulates their survival and mainten...

Background: Phylogenetic species trees are widely used in inferring evolutionary relationships. Existing software and algorithms mainly focus on phylogenetic inference. However, less attention has been paid to intermediate steps, such as processing extremely large sequences and preparing configure files to connect multiple software. When the speci...

Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F1FO ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial...

Mitochondrial metabolic plasticity is a key adaptive mechanism in response to changes in cellular metabolic demand. Changes in mitochondrial metabolic efficiency have been linked to pathophysiological conditions, including cancer, neurodegeneration, and obesity. The ubiquitously expressed DJ-1 (Parkinsonism-associated deglycase) is known as a Parki...

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most commonly used surgical treatment for Parkinson’s disease (PD). The disease-modifying aspects of DBS at a cellular level are not fully understood, and the key question of the effect of DBS on the degeneration of the dopaminergic (DA) neurons in the substantia nigra pars compac...

ATP synthase is a complex universal enzyme responsible for ATP synthesis across all kingdoms of life. The F-type ATP synthase has been suggested to have evolved from two functionally independent, catalytic (F1) and membrane bound (Fo), ancestral modules. While the modular evolution of the synthase is supported by studies indicating independent asse...

Direct and indirect functional links between proteins as well as their interactions as part of larger protein complexes or common signaling pathways may be predicted by analyzing the correlation of their evolutionary patterns. Based on phylogenetic profiling, here we present a highly scalable and time-efficient computational framework for predictin...

Hit rates of PPP predicted linkages among the MMM protein pairs The protein pairs with more homology across a wide range of species showed a higher hit rate at more stringent top ranks, indicating increased true linkage detection by PPP. The hit rate denotes the ratio between the number of linkages predicted by PPP and the number of MMM linkages.

Validation of PPP performance ROC curves and PR curves are generated by using another random negative reference dataset (A–B), complexes with less than 40 subunits (C–D), and a validation dataset from Ta and colleagues (Ta, Koskinen & Holm, 2011) (E–F).

The phylogenetic plot of selected mitochondrial proteins The two clusters consist of a group of proteins present among a wide range of species and a group that was almost exclusively present in Metazoa.

ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rod...

Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for ATP production by mitochondria, recent findings have confirmed that the c-subunit of the ATP synthase also houses a large conductance uncoupling channel, the m...

Neurons experience high metabolic demand during such processes as synaptic vesicle recycling, membrane potential maintenance and Ca(2+) exchange/extrusion. The energy needs of these events are met in large part by mitochondrial production of ATP through the process of oxidative phosphorylation. The job of ATP production by the mitochondria is perfo...

Mitochondrial ATP generation by oxidative phosphorylation combines the stepwise oxidation by the electron transport chain (ETC) of the reducing equivalents NADH and FADH2 with the generation of ATP by the ATP synthase. Recent studies show that the ATP synthase is not only essential for the generation of ATP but may also contribute to the formation...

B‐cell lymphoma‐extra large (Bcl‐xL) protein is an anti‐apoptotic member of the Bcl2 family. In contrast to its protective functions, Bcl‐xL is also capable of playing a pro‐apoptotic role. ΔN‐Bcl‐xL, the C‐terminal cleavage product of Bcl‐xL, is produced during brain ischemia and activates large conductance mitochondrial channel activity. We hypot...

Author Summary Improper functioning of the brain regions known as prefrontal cortex and amygdala is associated with the development of post-traumatic stress disorder. However, little is known about the molecular mechanisms that underlie this condition. We found that the expression of a protein kinase involved in cellular responses to stress, known...

Ion transport across the mitochondrial inner and outer membranes is central to mitochondrial function, including regulation of oxidative phosphorylation and cell death. Although required for adenosine triphosphate (ATP) production by mitochondria, recent findings have confirmed that the c-subunit of the ATP synthase also houses a large conductance...

ABT-737 is a pharmacological inhibitor of the anti-apoptotic Bcl-2 family protein, Bcl-xL. ABT-737 occupies the BH3-binding domain, supporting apoptosis of cancer cells. We have shown that ABT-737 lowers neuronal metabolic efficiency by inhibiting ATP synthase activity. However, we unexpectedly found that ABT-737 protects brains from ischemic injur...

Iron deficiency without anaemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival. We hypothesised that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy. Rats were fed an iron-deficient d...

Deep brain stimulation (DBS) surgery, targeting various regions of the brain such as the basal ganglia, thalamus, and subthalamic regions, is an effective treatment for several movement disorders that have failed to respond to medication. Recent progress in the field of DBS surgery has begun to extend the application of this surgical technique to o...

Degeneration of mesencephalic dopaminergic (mesDA) neurons is the pathological hallmark of Parkinson’s diseae. Study of the biological processes involved in physiological functions and vulnerability and death of these neurons is imparative to understanding the underlying causes and unraveling the cure for this common neurodegenerative disorder. Pri...

Inefficiency of oxidative phosphorylation can result from futile leak conductance through the inner mitochondrial membrane. Stress or injury may exacerbate this leak conductance, putting cells, and particularly neurons, at risk of dysfunction and even death when energy demand exceeds cellular energy production. Using a novel method, we have recentl...

Aims: B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth and synapse formation are indispensable for neuronal survival in development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes in...

Specific vulnerability and degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain is the pathological hallmark of Parkinson's disease. A number of transcription factors regulate the birth and development of this set of neurons and some remain constitutively expressed throughout life. These maintenance transcr...

Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cell Ca2+ dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction and cell death. The molecular identity of the mitochon...

Mitochondria are involved in many important cellular functions including metabolism, survival(1), development and, calcium signaling(2). Two of the most important mitochondrial functions are related to the efficient production of ATP, the energy currency of the cell, by oxidative phosphorylation, and the mediation of signals for programmed cell dea...

The progressive loss of midbrain dopaminergic neurons is the hallmark of Parkinson's disease (PD). Defects in mitochondrial electron transport and mitochondrial DNA replication predispose to the onset of PD. The protein products of several PD genes, including Parkin, Pink1 and DJ1 are known to localize to mitochondria; pathological mutations in the...

NADPH is an important component of the antioxidant defense system and a proposed mediator in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. An increase in the NADPH/NADP(+) ratio has been reported to occur within minutes following the rise in glucose concentration in β-cells. However, 30 min following the increase in glucose,...

Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic ef...