Publications
61 results found
Alavian KN, Dworetzky SI, Bonanni L, et al., 2015, The Mitochondrial Complex V-Associated Large-Conductance Inner Membrane Current Is Regulated by Cyclosporine and Dexpramipexole, MOLECULAR PHARMACOLOGY, Vol: 87, Pages: 1-8, ISSN: 0026-895X
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- Citations: 37
Jonas EA, Porter GA, Alavian KN, 2014, BcI-xL in neuroprotection and plasticity, FRONTIERS IN PHYSIOLOGY, Vol: 5, ISSN: 1664-042X
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- Citations: 35
Alavian KN, Beutner G, Lazrove E, et al., 2014, An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore, Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 10580-10585, ISSN: 0027-8424
Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (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 mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the FO of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca2+ enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F1, providing a mechanism for mPTP opening. In contrast, recombinant F1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca2+-induced IMM depolarization and inhibits Ca2+ and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.
Alavian KN, Jeddi S, Naghipour SI, et al., 2014, The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed, JOURNAL OF BIOMEDICAL SCIENCE, Vol: 21, ISSN: 1021-7770
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- Citations: 43
Jonas E, Sacchetti S, Park H-A, et al., 2014, The C-Subunit of the ATP Synthase Forms the Pore of the PTP, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 3A-4A, ISSN: 0006-3495
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- Citations: 1
Li H, Alavian KN, Lazrove E, et al., 2013, A Bcl-x(L)-Drp1 complex regulates synaptic vesicle membrane dynamics during endocytosis, Nature Cell Biology, Vol: 15, Pages: 773-785, ISSN: 1465-7392
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 by increasing ATP availability from mitochondria. We now find, that Bcl-xL directly regulates endocytic vesicle retrieval in hippocampal neurons through protein–protein interaction with components of the clathrin complex. Our evidence suggests that, during synaptic stimulation, Bcl-xL translocates to clathrin-coated pits in a calmodulin-dependent manner and forms a complex with the GTPase Drp1, Mff and clathrin. Depletion of Drp1 produces misformed endocytic vesicles. Mutagenesis studies suggest that formation of the Bcl-xL–Drp1 complex is necessary for the enhanced rate of vesicle endocytosis produced by Bcl-xL, thus providing a mechanism for presynaptic plasticity.
Sacchetti S, Alavian KN, Lazrove E, et al., 2013, F<sub>1</sub>F<sub>O</sub> ATPase Vesicle Preparation and Technique for Performing Patch Clamp Recordings of Submitochondrial Vesicle Membranes, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X
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- Citations: 6
Jonas EA, Lazrove E, Nabili P, et al., 2013, DJ1 regulates Neuronal Mitochondrial Bioenergetic Efficiency, 57th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 657A-657A, ISSN: 0006-3495
Gray JP, Alavian KN, Jonas EA, et al., 2012, NAD kinase regulates the size of the NADPH pool and insulin secretion in pancreatic β-cells, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 303, Pages: E191-E199, ISSN: 0193-1849
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- Citations: 25
Ofengeim D, Chen Y-B, Miyawaki T, et al., 2012, N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death, Nature Neuroscience, Vol: 15, Pages: 574-580, ISSN: 1097-6256
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-xL inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-xL is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-xL. We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-xL–induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-xL, we generated knock-in mice expressing a caspase-resistant form of Bcl-xL. The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-xL could be a potentially important therapeutic target in ischemic brain injury.
Alavian KN, Dworetzky SI, Bonanni L, et al., 2012, Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency, BRAIN RESEARCH, Vol: 1446, Pages: 1-11, ISSN: 0006-8993
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- Citations: 44
Alavian KN, Gribkoff V, Jonas EA, et al., 2012, Compounds and methods of modulating mitochondrial bioenergetic efficiency through an interaction with atp synthase (complex v) and its subunits, WO 2011150221 A3
The present invention provides, in part, methods of identifying compounds that can bind to an ATP synthase complex, increase bioenergetic efficiency, decrease oxygen consumption or the rate thereof, increase oxygen utilization efficiency, increase cell survival or any combination thereof, and methods of using compounds and/or identified compounds to increase bioenergetic efficiency, increase oxygen utilization efficiency, decrease oxygen consumption, increase cell survival, or any combination thereof.
Alavian KN, Lazrove E, Nabili P, et al., 2012, The C-Subunit Ring of the F1FO ATP Synthase Constitutes a Leak Channel that Regulates Cellular Metabolic Efficiency by Counteracting the HD Translocator, 56th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 571A-571A, ISSN: 0006-3495
Alavian KN, Li H, Collis L, et al., 2011, Bcl-x<sub>L</sub> regulates metabolic efficiency of neurons through interaction with the mitochondrial F<sub>1</sub>F<sub>O</sub> ATP synthase (vol 13, pg 1224, 2011), NATURE CELL BIOLOGY, Vol: 13, Pages: 1383-1383, ISSN: 1465-7392
Chen Y-B, Aon MA, Hsu Y-T, et al., 2011, Bcl-x(L) regulates mitochondrial energetics by stabilizing the inner membrane potential, The Journal of Cell Biology, Vol: 195, Pages: 263-276, ISSN: 0021-9525
Mammalian Bcl-xL protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Bax-induced outer membrane permeabilization. Contrary to expectation, we found by electron microscopy and biochemical approaches that endogenous Bcl-xL also localized to inner mitochondrial cristae. Two-photon microscopy of cultured neurons revealed large fluctuations in inner mitochondrial membrane potential when Bcl-xL was genetically deleted or pharmacologically inhibited, indicating increased total ion flux into and out of mitochondria. Computational, biochemical, and genetic evidence indicated that Bcl-xL reduces futile ion flux across the inner mitochondrial membrane to prevent a wasteful drain on cellular resources, thereby preventing an energetic crisis during stress. Given that F1FO–ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase β subunit in a screen for Bcl-xL–binding partners, we tested and found that Bcl-xL failed to protect β subunit–deficient yeast. Thus, by bolstering mitochondrial energetic capacity, Bcl-xL may contribute importantly to cell survival independently of other Bcl-2 family proteins.
Alavian KN, Li H, Collis L, et al., 2011, Bcl-x(L) regulates metabolic efficiency of neurons through interaction with the mitochondrial F1F0 ATP synthase, Nature Cell Biology, Vol: 13, Pages: 1224-1233, ISSN: 1465-7392
Anti-apoptotic Bcl2 family proteins such as Bcl-xL protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-xL enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-xLinteracts directly with the β-subunit of the F1FO ATP synthase, decreasing an ion leak within the F1FO ATPase complex and thereby increasing net transport of H+ by F1FO during F1FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F1FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-xL protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-xL-expressing neurons.
Alavian KN, Li H, Nabili P, et al., 2011, BCL-Xl Regulates ATP Synthase and Synaptic Efficiency, 64th Annual Meeting of the Society-of-General-Physiologists, Publisher: ROCKEFELLER UNIV PRESS, Pages: 9A-9A, ISSN: 0022-1295
Sanchez CE, Tierney TS, Gale JT, et al., 2011, Recombinant adeno-associated virus type 2 pseudotypes: comparing safety, specificity, and transduction efficiency in the primate striatum Laboratory investigation, JOURNAL OF NEUROSURGERY, Vol: 114, Pages: 672-680, ISSN: 0022-3085
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- Citations: 16
Sacchetti S, Dworetzky SI, Alavian KN, et al., 2011, Decrease in a Leak Conductance Associated with Mitochondrial Complex V and Improved Bioenergetic Efficiency may Underlie Cytoprotection of at-Risk Neurons by Dexpramipexole, 55th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 459-459, ISSN: 0006-3495
Alavian KN, Li H, Sacchetti S, et al., 2011, Bcl-xL Determines the Metabolic Efficiency of Neurons, through Interaction with Mitochondrial ATP Synthase, 55th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 459-459, ISSN: 0006-3495
Vahedi S, Rajabian M, Misaghian A, et al., 2010, Parkinson's disease candidate gene prioritization based on expression profile of midbrain dopaminergic neurons, Journal of Biomedical Science, Vol: 17, Pages: 1-5, ISSN: 1021-7770
BackgroundParkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the indentified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes.MethodsIn this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease.ResultsMerging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies.
Chung CY, Licznerski P, Alavian KN, et al., 2010, The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons, BRAIN, Vol: 133, Pages: 2022-2031, ISSN: 0006-8950
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- Citations: 41
Alavian K, Collis L, Li H, et al., 2010, BCL-xL Regulates ATP Synthase and Synaptic Efficiency, BIOPHYSICAL JOURNAL, Vol: 98, Pages: 465A-465A, ISSN: 0006-3495
Pruszak J, Ludwig W, Blak A, et al., 2009, CD15, CD24, and CD29 Define a Surface Biomarker Code for Neural Lineage Differentiation of Stem Cells, STEM CELLS, Vol: 27, Pages: 2928-2940, ISSN: 1066-5099
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- Citations: 176
Alavian KN, Sgado P, Alberi L, et al., 2009, Elevated P75(NTR) expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression, Neural Development, Vol: 4, Pages: 1-13, ISSN: 1749-8104
BackgroundThe homeodomain transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic (mesDA) neurons in a cell-autonomous and gene-dose-dependent manner. Homozygote mutant mice, deficient of both genes (En1-/-;En2-/-), die at birth and exhibit a loss of all mesDA neurons by mid-gestation. In heterozygote animals (En1+/-;En2-/-), which are viable and fertile, postnatal maintenance of the nigrostriatal dopaminergic system is afflicted, leading to a progressive degeneration specific to this subpopulation and Parkinson's disease-like molecular and behavioral deficits.ResultsIn this work, we show that the dose of Engrailed is inversely correlated to the expression level of the pan-neurotrophin receptor gene P75NTR(Ngfr). Loss of mesDA neurons in the Engrailed-null mutant embryos is caused by elevated expression of this neurotrophin receptor: Unusually, in this case, the cell death signal of P75NTR is mediated by suppression of Erk1/2 (extracellular-signal-regulated kinase 1/2) activity. The reduction in expression of Engrailed, possibly related to the higher levels of P75NTR, also decreases mitochondrial stability. In particular, the dose of Engrailed determines the sensitivity to cell death induced by the classic Parkinson-model toxin MPTP and to inhibition of the anti-apoptotic members of the Bcl-2 family of proteins.ConclusionOur study links the survival function of the Engrailed genes in developing mesDA neurons to the regulation of P75NTRand the sensitivity of these neurons to mitochondrial insult. The similarities to the disease etiology in combination with the nigral phenotype of En1+/-;En2-/- mice suggests that haplotype variations in the Engrailed genes and/or P75NTRthat alter their expression levels could, in part, determine susceptibility to Parkinson's disease.
Alavian KN, Simon HH, 2009, Linkage of cDNA expression profiles of mesencephalic dopaminergic neurons to a genome-wide in situ hybridization database, Molecular Neurodegeneration, Vol: 4, Pages: 1-4, ISSN: 1750-1326
Midbrain dopaminergic neurons are involved in control of emotion, motivation and motor behavior. The loss of one of the subpopulations, substantia nigra pars compacta, is the pathological hallmark of one of the most prominent neurological disorders, Parkinson's disease. Several groups have looked at the molecular identity of midbrain dopaminergic neurons and have suggested the gene expression profile of these neurons. Here, after determining the efficiency of each screen, we provide a linked database of the genes, expressed in this neuronal population, by combining and comparing the results of six previous studies and verification of expression of each gene in dopaminergic neurons, using the collection of in situ hybridization in the Allen Brain Atlas.
Simon HH, Alavian KN, 2009, Transcriptional Regulation of Their Survival: The <i>Engrailed</i> Homeobox Genes, DEVELOPMENT AND ENGINEERING OF DOPAMINE NEURONS, Vol: 651, Pages: 66-72, ISSN: 0065-2598
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- Citations: 2
Alavian KN, Scholz C, Simon HH, 2008, Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and death, MOVEMENT DISORDERS, Vol: 23, Pages: 319-328, ISSN: 0885-3185
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- Citations: 67
Sgadò P, Alberi L, Gherbassi D, et al., 2006, Slow progressive degeneration of nigral dopaminergic neurons in postnatal <i>Engrailed</i> mutant mice, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 103, Pages: 15242-15247, ISSN: 0027-8424
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- Citations: 105
Simon HH, Sgado P, Alavian KN, et al., 2006, The role of the engrailed transcription factors in the survival of mesencephalic dopaminergic neurons, 1st World Parkinson Congress, Publisher: WILEY-LISS, Pages: S5-S6, ISSN: 0885-3185
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