UA cloudflare authentication

Browsing by Author "Hamamichi, Shusei"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Clioquinol promotes the degradation of metal-dependent amyloid-beta (A beta) oligomers to restore endocytosis and ameliorate A beta toxicity
    (National Academy of the Sciences, 2014) Matlack, Kent E. S.; Tardiff, Daniel F.; Narayan, Priyanka; Hamamichi, Shusei; Caldwell, Kim A.; Caldwell, Guy A.; Lindquist, Susan; Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Alabama Tuscaloosa; Howard Hughes Medical Institute
    Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-beta peptide (A beta) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by A beta has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of A beta toxicity where the A beta peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic A beta 1-42 peptide forms more oligomers and is more toxic than A beta 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of similar to 140,000 compounds for rescue of A beta toxicity. Of similar to 30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce A beta burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of A beta secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced A beta peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent A beta oligomer formation contributes to A beta toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the A beta yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.
  • Thumbnail Image
    Item
    Functional Links Between A beta Toxicity, Endocytic Trafficking, and Alzheimer's Disease Risk Factors in Yeast
    (American Association for the Advancement of Science, 2011) Treusch, Sebastian; Hamamichi, Shusei; Goodman, Jessica L.; Matlack, Kent E. S.; Chung, Chee Yeun; Baru, Valeriya; Shulman, Joshua M.; Parrado, Antonio; Bevis, Brooke J.; Valastyan, Julie S.; Han, Haesun; Lindhagen-Persson, Malin; Reiman, Eric M.; Evans, Denis A.; Bennett, David A.; Olofsson, Anders; DeJager, Philip L.; Tanzi, Rudolph E.; Caldwell, Kim A.; Caldwell, Guy A.; Lindquist, Susan; Massachusetts Institute of Technology (MIT); Whitehead Institute; Howard Hughes Medical Institute; University of Alabama Tuscaloosa; Harvard University; Brigham & Women's Hospital; Harvard Medical School; Broad Institute; Massachusetts General Hospital; Umea University; Translational Genomics Research Institute; University of Arizona; Banner Research; Banner Health; Banner Alzheimer's Institute; Rush University
    A beta (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled A beta toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to A beta was previously unknown. The factors identified in yeast modified A beta toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, A beta impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between A beta, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.
  • Thumbnail Image
    Item
    The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson's Models
    (Cell Press, 2014) Knight, Adam L.; Yan, Xiaohui; Hamamichi, Shusei; Ajjuri, Rami R.; Mazzulli, Joseph R.; Zhang, Mike W.; Daigle, J. Gavin; Zhang, Siyuan; Borom, Akeem R.; Roberts, Lindsay R.; Lee, S. Kyle; DeLeon, Susan M.; Viollet-Djelassi, Coralie; Krainc, Dimitri; O'Donnell, Janis M.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham; Harvard University; Massachusetts General Hospital; University of Oxford; Wellcome Centre for Human Genetics; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute
    Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and life-span extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of alpha-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from alpha-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
  • Thumbnail Image
    Item
    Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models
    (Oxford University Press, 2011) Liu, Zhaohui; Hamamichi, Shusei; Lee, Byoung Dae; Yang, Dejun; Ray, Arpita; Caldwell, Guy A.; Caldwell, Kim A.; Dawson, Ted M.; Smith, Wanli W.; Dawson, Valina L.; University of Alabama Tuscaloosa; University of Maryland Baltimore; Johns Hopkins University; University of Alabama Birmingham
    Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD.
  • Thumbnail Image
    Item
    Protective Role of DNJ-27/ERdj5 in Caenorhabditis elegans Models of Human Neurodegenerative Diseases
    (Mary Ann Liebert, 2014) Munoz-Lobato, Fernando; Jesus Rodriguez-Palero, Maria; Jose Naranjo-Galindo, Francisco; Shephard, Freya; Gaffney, Christopher J.; Szewczyk, Nathaniel J.; Hamamichi, Shusei; Caldwell, Kim A.; Caldwell, Guy A.; Link, Chris D.; Miranda-Vizuete, Antonio; Consejo Superior de Investigaciones Cientificas (CSIC); Universidad Pablo de Olavide; CSIC - Andalusian Center for Developmental Biology (CABD); University of Sevilla; CSIC-JA-USE - Instituto de Biomedicina de Sevilla (IBIS); Virgen del Rocio University Hospital; University of Nottingham; University of Alabama Tuscaloosa; University of Colorado Boulder
    Aims: Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases. Results: We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human -amyloid peptide (A), -synuclein (-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human A and -syn peptides in these worm models. Innovation: We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human A, -syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. Conclusion: Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND. Antioxid. Redox Signal. 20, 217-235.
  • Thumbnail Image
    Item
    Systemic RNA Interference Defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans
    (PLOS, 2022) Gaeta, Anthony L.; Nourse, J. Brucker, Jr.; Willicott, Karolina; Mckay, Luke E.; Keogh, Candice M.; Peter, Kylie; Russell, Shannon N.; Hamamichi, Shusei; Berkowitz, Laura A.; Caldwell, Kim A.; Caldwell, Guy A.; University of Alabama Tuscaloosa; University of Alabama Birmingham; Tottori University
    The fine-tuning of gene expression is critical for all cellular processes; aberrations in this activity can lead to pathology, and conversely, resilience. As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode Caenorhabditis elegans, deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson's disease (PD). Specifically, the loss of either the sid-1 or sid-3 genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic C. elegans strain wherein overexpression of human alpha-synuclein (alpha-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA, mir-2, attenuates alpha-syn neurotoxicity; suggesting that the native targets of mir-2-dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple mir-2 targets enhanced alpha-syn-induced DA neurodegeneration. Moreover, we demonstrate that mir-2 overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly, sid-1 mutants retained mir-2-induced enhancement of neurodegeneration. Transcriptomic analysis of alpha-syn animals with and without a sid-1 mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was pgp-8, encoding a P-glycoprotein-related ABC transporter. Notably, sid-1; pgp-8 double mutants abolished the neurodegeneration resulting from intestinal mir-2 overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.