PMID- 30141626
OWN - NLM
STAT- MEDLINE
DCOM- 20190726
LR  - 20200309
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Print)
IS  - 1554-8929 (Linking)
VI  - 13
IP  - 10
DP  - 2018 Oct 19
TI  - A Chemical Biology Approach to Model Pontocerebellar Hypoplasia Type 1B (PCH1B).
PG  - 3000-3010
LID - 10.1021/acschembio.8b00745 [doi]
AB  - Mutations of EXOSC3 have been linked to the rare neurological disorder known as 
      Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative 
      RNA-binding structural cap proteins that guide RNA into the RNA exosome, the 
      cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich 
      RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale 
      thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 
      for long and short G-rich RNA sequences. Although several PCH1B-causing mutations 
      in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they 
      exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test 
      the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants 
      may be phenocopied by small molecules, we performed an in-silico screen of 50 000 
      small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to 
      assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We 
      identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), 
      which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear 
      magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a 
      concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 
      50% reduction in the cerebellum and an abnormally curved spine in zebrafish 
      embryos. This compound also induced modification of zebrafish RNA expression 
      levels similar to that observed with a morpholino against EXOSC3. To our 
      knowledge, this is the first example of a small molecule obtained by rational 
      design that models the abnormal developmental effects of a neurodegenerative 
      disease in a whole organism.
FAU - Francois-Moutal, Liberty
AU  - Francois-Moutal L
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
AD  - Center for Innovation in Brain Science , Tucson , Arizona 85721 , United States.
FAU - Jahanbakhsh, Shahriyar
AU  - Jahanbakhsh S
AD  - Department of Chemistry and Biochemistry , University of California , Los Angeles 
      , California 90095 , United States.
FAU - Nelson, Andrew D L
AU  - Nelson ADL
AUID- ORCID: 0000-0001-9896-1739
AD  - School of Plant Sciences , University of Arizona , Tucson , Arizona 85721 , 
      United States.
FAU - Ray, Debashish
AU  - Ray D
AD  - Donnelly Centre , University of Toronto , Toronto , Canada M5S 3E1.
FAU - Scott, David D
AU  - Scott DD
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
AD  - Center for Innovation in Brain Science , Tucson , Arizona 85721 , United States.
FAU - Hennefarth, Matthew R
AU  - Hennefarth MR
AD  - Department of Chemistry and Biochemistry , University of California , Los Angeles 
      , California 90095 , United States.
FAU - Moutal, Aubin
AU  - Moutal A
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
FAU - Perez-Miller, Samantha
AU  - Perez-Miller S
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
AD  - Center for Innovation in Brain Science , Tucson , Arizona 85721 , United States.
FAU - Ambrose, Andrew J
AU  - Ambrose AJ
AUID- ORCID: 0000-0002-2932-4514
AD  - Pharmacology and Toxicology, School of Pharmacy , University of Arizona , Tucson 
      , Arizona 85724 , United States.
FAU - Al-Shamari, Ahmed
AU  - Al-Shamari A
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
FAU - Coursodon, Philippe
AU  - Coursodon P
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
FAU - Meechoovet, Bessie
AU  - Meechoovet B
AD  - Neurogenomics Division , TGen , Phoenix , Arizona 85004 , United States.
FAU - Reiman, Rebecca
AU  - Reiman R
AD  - Neurogenomics Division , TGen , Phoenix , Arizona 85004 , United States.
FAU - Lyons, Eric
AU  - Lyons E
AD  - School of Plant Sciences , University of Arizona , Tucson , Arizona 85721 , 
      United States.
FAU - Beilstein, Mark
AU  - Beilstein M
AD  - School of Plant Sciences , University of Arizona , Tucson , Arizona 85721 , 
      United States.
FAU - Chapman, Eli
AU  - Chapman E
AD  - Pharmacology and Toxicology, School of Pharmacy , University of Arizona , Tucson 
      , Arizona 85724 , United States.
FAU - Morris, Quaid D
AU  - Morris QD
AD  - Donnelly Centre , University of Toronto , Toronto , Canada M5S 3E1.
AD  - Department of Molecular Genetics , University of Toronto , Toronto , Canada M5S 
      1A8.
AD  - Department of Computer Science , University of Toronto , Toronto , Canada M5S 
      2E4.
AD  - Department of Electrical and Computer Engineering , University of Toronto , 
      Toronto , Canada M5S3G4.
FAU - Van Keuren-Jensen, Kendall
AU  - Van Keuren-Jensen K
AD  - Neurogenomics Division , TGen , Phoenix , Arizona 85004 , United States.
FAU - Hughes, Timothy R
AU  - Hughes TR
AD  - Donnelly Centre , University of Toronto , Toronto , Canada M5S 3E1.
AD  - Department of Molecular Genetics , University of Toronto , Toronto , Canada M5S 
      1A8.
FAU - Khanna, Rajesh
AU  - Khanna R
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
AD  - Center for Innovation in Brain Science , Tucson , Arizona 85721 , United States.
FAU - Koehler, Carla
AU  - Koehler C
AD  - Department of Chemistry and Biochemistry , University of California , Los Angeles 
      , California 90095 , United States.
FAU - Jen, Joanna
AU  - Jen J
AD  - Mount Sinai , New York , New York 10029 , United States.
FAU - Gokhale, Vijay
AU  - Gokhale V
AD  - Bio5 Institute , University of Arizona , Tucson , Arizona , United States.
FAU - Khanna, May
AU  - Khanna M
AUID- ORCID: 0000-0002-9989-6374
AD  - Department of Pharmacology , College of Medicine, University of Arizona , Tucson 
      , Arizona 85724 , United States.
AD  - Center for Innovation in Brain Science , Tucson , Arizona 85721 , United States.
LA  - eng
GR  - R01 GM061721/GM/NIGMS NIH HHS/United States
GR  - R01 HG008613/HG/NHGRI NIH HHS/United States
GR  - T32 GM008804/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180906
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (EXOSC3 protein, human)
RN  - 0 (Isoquinolines)
RN  - 0 (RNA-Binding Proteins)
RN  - 63231-63-0 (RNA)
RN  - EC 3.1.- (Exosome Multienzyme Ribonuclease Complex)
RN  - Pontocerebellar Hypoplasia Type 1
MH  - Animals
MH  - Atrophy
MH  - Cerebellum/pathology
MH  - *Disease Models, Animal
MH  - Down-Regulation
MH  - Exosome Multienzyme Ribonuclease Complex/chemistry/genetics/*metabolism
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Isoquinolines/metabolism/*pharmacology/*toxicity
MH  - Molecular Docking Simulation
MH  - Mutation
MH  - Olivopontocerebellar Atrophies/chemically induced/*genetics/pathology
MH  - Phenotype
MH  - Protein Binding
MH  - Protein Domains
MH  - RNA/*metabolism
MH  - RNA-Binding Proteins/chemistry/genetics/*metabolism
MH  - Spinal Curvatures/chemically induced
MH  - Transcriptome/drug effects
MH  - Up-Regulation
MH  - Zebrafish/*abnormalities
PMC - PMC6504997
MID - NIHMS1016684
COIS- The authors declare no competing financial interest.
EDAT- 2018/08/25 06:00
MHDA- 2019/07/28 06:00
PMCR- 2019/05/08
CRDT- 2018/08/25 06:00
PHST- 2018/08/25 06:00 [pubmed]
PHST- 2019/07/28 06:00 [medline]
PHST- 2018/08/25 06:00 [entrez]
PHST- 2019/05/08 00:00 [pmc-release]
AID - 10.1021/acschembio.8b00745 [doi]
PST - ppublish
SO  - ACS Chem Biol. 2018 Oct 19;13(10):3000-3010. doi: 10.1021/acschembio.8b00745. 
      Epub 2018 Sep 6.