A5052705491- Cancer, Hypoxia, and Metabolism
- PARP inhibition in cancer therapy
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Cell death mechanisms and regulation
- Epigenetics and DNA Methylation
- Nuclear Receptors and Signaling
- Integrated Circuits and Semiconductor Failure Analysis
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA modifications and cancer
- Neuroscience and Neuropharmacology Research
- Autophagy in Disease and Therapy
- Alzheimer's disease research and treatments
- Sirtuins and Resveratrol in Medicine
- Receptor Mechanisms and Signaling
- Toxin Mechanisms and Immunotoxins
- DNA Repair Mechanisms
- Calcium signaling and nucleotide metabolism
- Cardiac Ischemia and Reperfusion
- Medical Imaging Techniques and Applications
- Traumatic Brain Injury Research
- Spinal Cord Injury Research
- RNA regulation and disease
- Neurological diseases and metabolism
- Electrostatic Discharge in Electronics
University of Alabama at Birmingham
2017-2025
University of Alabama
2024-2025
Weatherford College
2022
Johns Hopkins Medicine
2009-2021
Johns Hopkins University
2010-2021
Université Laval
2019
Otto-von-Guericke University Magdeburg
2004-2012
Stem Cell Institute
2011
Neurology, Inc
2006-2008
Institute of Pathology Celle
2006-2008
Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation. How PARP-1 activation leads AIF release not known. Here we identify PAR polymer as signal that induces of AIF. and translocation nucleus. glycohydrolase, which degrades polymer, prevents PARP-1-dependent release. Cells with reduced levels are resistant cytotoxicity. These results reveal an AIF-releasing plays...
INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disorder and leads to slowness of movement, tremor, rigidity, and, in later stages PD, cognitive impairment. Pathologically, PD characterized by accumulation α-synuclein Lewy bodies neurites. There degeneration neurons throughout nervous system, with dopamine substantia nigra pars compacta leading major symptoms PD. RATIONALE In brains patients, pathologic seems spread from cell via self-amplification,...
Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various models cellular injury. Here, we identify (PAR) polymer, product PARP-1 activity, as previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation by glycohydrolase (PARG) or phosphodiesterase 1 prevents polymer-induced death. PARP-1-dependent, NMDA excitotoxicity cortical neurons reduced neutralizing antibodies overexpression PARG....
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations LRRK2 initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result increased activity. Functional and disease-associated conserved residues reveal critical link between intrinsic guanosine triphosphatase (GTPase) activity downstream requires GTPase...
The PARK8 gene responsible for late-onset autosomal dominant Parkinson's disease encodes a large novel protein of unknown biological function termed leucine-rich repeat kinase 2 (LRRK2). studies herein explore the localization LRRK2 in mammalian brain.Polyclonal antibodies generated against amino or carboxy termini were used to examine biochemical, subcellular, and immunohistochemical distribution LRRK2.LRRK2 is detected rat brain as an approximate 280kDa by Western blot analysis....
Poly(ADP-ribose) binds to apoptosis-inducing factor trigger its release from mitochondria and induce cell death.
PAR promotes α-synuclein toxicity How pathologic (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see Perspective by Brundin and Wyse). They found that α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) inhibition PARP or knockout PARP-1 protected mice from pathology. The generation PFF–induced activation converted PFF a strain was 25-fold...
DNA damage-activated nuclease identified Cells that experience stresses and accumulate excessive damage to undergo cell death mediated by a nuclear enzyme known as PARP-1. During this process, apoptosis-inducing factor (AIF) translocates the nucleus activates one or more nucleases cleave DNA. Wang et al. found macrophage migration inhibitory (MIF) is an AIF-associated endonuclease contributes PARP-1-induced fragmentation (see Perspective Jonas). In mouse neurons in culture, loss of MIF...
Significance Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety organ systems. It has long been thought that the caused by excessive PARP occurs through catalytic consumption NAD + followed reduction ATP and bioenergetic collapse. This study shows collapse not but PAR-dependent inhibition hexokinase activity leading defects glycolysis. These results are consistent with notion induced (parthanatos) an active cell-death program...
Ubiquitin mediated protein degradation is crucial for regulation of cell signaling and quality control. Poly(ADP-ribose) (PAR) a cell-signaling molecule that mediates changes in function through binding at PAR sites. Here we characterize the protein, Iduna, show it PAR-dependent ubiquitin E3 ligase. Iduna’s ligase activity requires because point mutations Y156A R157A eliminate activity. also an intact really interesting new gene (RING) domain Iduna possessing either H54A or C60A devoid...
Intratumoral hypoxia stimulates enrichment of breast cancer stem cells (BCSC), which are critical for metastasis and patient mortality. Here we report a metabolic adaptation that is required hypoxia-induced BCSC metastasis. Hypoxia-inducible factors coordinately regulate expression genes encoding phosphoglycerate dehydrogenase (PHGDH) five downstream enzymes in the serine synthesis pathway mitochondrial one-carbon (folate) cycle. RNAi-mediated silencing PHGDH both estrogen receptor-positive...
Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of is thought contribute sporadic PD. Adult knockout the ventral midbrain mice leads an age-dependent loss dopamine neurons that dependent on accumulation interacting substrate (PARIS), zinc finger protein 746 (ZNF746), its transcriptional repression PGC-1α. Here we show adult mouse decreases mitochondrial size, number, markers consistent with a defect biogenesis. This decrease mass...
Melatonin, the secretory product of pineal gland, is known to be neuroprotective in cerebral ischemia, which so far mostly attributed its antioxidant properties. Here we show that melatonin directly inhibits mitochondrial permeability transition pore (mtPTP). mtPTP contributes pathology ischemia by releasing calcium and cytochrome c (cyt c) from mitochondria. Consistently, NMDA-induced rises were diminished cultured mouse striatal neurons, similar pattern seen with cyclosporine A (CsA). When...
Stroke is a leading cause of death and disability. The pathophysiological mechanisms associated with stroke are very complex not fully understood. Lysosomal function has vital physiological in the maintenance cellular homeostasis. In neurons, CTSD (cathepsin D) an essential protease involved regulation proteolytic activity lysosomes. Loss leads to lysosomal dysfunction accumulation different proteins implicated neurodegenerative diseases. cerebral ischemia, role clearly defined. We used...
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and animal or cellular models of PD. The PGC-1α the function survival substantia nigra pars compacta (SNpc) dopamine neurons not clear. Here we find that there are four different isoforms expressed SH-SY5Y cells, these across subregions mouse brain. Adult conditional knock-out mice show...
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have fibrotic repair, but contribution of MCU macrophage metabolism not known. Here, we show that regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic to fatty acid oxidation (FAO) macrophages. regulated PGC-1α...
Cellular stress can lead to several human disease pathologies due aberrant cell death. The p53 family (tp53, tp63, and tp73) downstream transcriptional apoptotic target genes (PUMA/BBC3 NOXA/PMAIP1) have been implicated as mediators of signals. To evaluate the importance key response components in vivo, we generated zebrafish null alleles puma, noxa, p53, p63, p73. Utilizing these genetic mutants, deciphered that genotoxic requires but not p73, or noxa. We also identified a delayed secondary...
Sirtuin 3 (SIRT3) is an NAD+ dependent deacetylase that resides primarily in mitochondria and functions to maintain mitochondrial homeostasis under stress. SIRT3 expression has been observed change a number of different stresses multiple tissues model systems. Inconsistencies the literature with regards how when protein levels indicates mechanism regulation multi-faceted. Alterations have experimental models cellular stress, however effect these changes on health remain unknown. Neurons are...
Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role the pathogenesis Parkinson's disease (PD). PARKIN regulates many aspects mitochondrial quality control including autophagy (mitophagy) biogenesis. Defects mitophagy have been hypothesized to predominant dopamine (DA) neurons PD. Here, we show that although there are defects human DA lacking deficits primarily due biogenesis driven by upregulation PARIS subsequent downregulation PGC-1α. CRISPR/Cas9 knockdown...