PMID- 32632005
OWN - NLM
STAT- MEDLINE
DCOM- 20200914
LR  - 20240329
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 29
DP  - 2020 Jul 21
TI  - Calpain inhibitor and ibudilast rescue beta cell functions in a cellular model of 
      Wolfram syndrome.
PG  - 17389-17398
LID - 10.1073/pnas.2007136117 [doi]
AB  - Wolfram syndrome is a rare multisystem disease characterized by childhood-onset 
      diabetes mellitus and progressive neurodegeneration. Most cases are attributed to 
      pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently 
      is no disease-modifying treatment for Wolfram syndrome, as the molecular 
      consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the 
      first diagnosed symptom of Wolfram syndrome, we aimed to further examine the 
      functions of WFS1 in pancreatic beta cells in the context of hyperglycemia. Knockout 
      (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and 
      protein kinase B/Akt signaling and, subsequently, decreased cell viability and 
      glucose-stimulated insulin secretion. Targeting calcium homeostasis with 
      reexpression of WFS1, overexpression of WFS1's interacting partner neuronal 
      calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast 
      reversed deficits observed in WFS1-KO cells. Collectively, our findings provide 
      insight into the disease mechanism of Wolfram syndrome and highlight new targets 
      and drug candidates to facilitate the development of a treatment for this 
      disorder and similar diseases.
FAU - Nguyen, Lien D
AU  - Nguyen LD
AUID- ORCID: 0000-0001-8096-1570
AD  - Department of Pharmacology, Yale University, New Haven, CT 06520.
AD  - Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520.
FAU - Fischer, Tom T
AU  - Fischer TT
AUID- ORCID: 0000-0002-2138-9102
AD  - Department of Pharmacology, Yale University, New Haven, CT 06520.
AD  - Institute of Pharmacology, University of Heidelberg, 69117 Heidelberg, Germany.
FAU - Abreu, Damien
AU  - Abreu D
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO 63110.
AD  - Medical Scientist Training Program, Washington University School of Medicine, St. 
      Louis, MO 63110.
FAU - Arroyo, Alfredo
AU  - Arroyo A
AD  - Department of Pharmacology, Yale University, New Haven, CT 06520.
FAU - Urano, Fumihiko
AU  - Urano F
AUID- ORCID: 0000-0002-9944-6293
AD  - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid 
      Research, Washington University School of Medicine, St. Louis, MO 63110.
AD  - Department of Pathology and Immunology, Washington University School of Medicine, 
      St. Louis, MO 63110.
FAU - Ehrlich, Barbara E
AU  - Ehrlich BE
AUID- ORCID: 0000-0001-9657-9704
AD  - Department of Pharmacology, Yale University, New Haven, CT 06520; 
      barbara.ehrlich@yale.edu.
AD  - Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520.
LA  - eng
GR  - UH3 TR002065/TR/NCATS NIH HHS/United States
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
GR  - F30 DK111070/DK/NIDDK NIH HHS/United States
GR  - P01 DK057751/DK/NIDDK NIH HHS/United States
GR  - P60 DK020579/DK/NIDDK NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - R01 DK112921/DK/NIDDK NIH HHS/United States
GR  - UH2 TR002065/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200706
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Calmodulin-Binding Proteins)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Pyridines)
RN  - 0 (WFS1 protein, rat)
RN  - 0 (calpain inhibitors)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - M0TTH61XC5 (ibudilast)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Calcium/metabolism
MH  - Calmodulin-Binding Proteins/genetics/*metabolism
MH  - Cell Survival/drug effects
MH  - Cysteine Proteinase Inhibitors/*pharmacology
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum/metabolism
MH  - Gene Expression Regulation
MH  - Gene Knockout Techniques
MH  - Glycoproteins
MH  - Homeostasis
MH  - Hyperglycemia
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/*drug effects
MH  - Membrane Proteins/genetics/*metabolism
MH  - Pyridines/*pharmacology
MH  - Receptor, Insulin
MH  - Transcriptome
MH  - Wolfram Syndrome/*drug therapy/genetics
PMC - PMC7382278
OTO - NOTNLM
OT  - Akt
OT  - calcium signaling
OT  - cell viability
OT  - diabetes
OT  - ibudilast
COIS- Competing interest statement: B.E.E. is a cofounder of Osmol Therapeutics, a 
      company that is targeting NCS1 for therapeutic purposes.
EDAT- 2020/07/08 06:00
MHDA- 2020/09/15 06:00
PMCR- 2021/01/06
CRDT- 2020/07/08 06:00
PHST- 2020/07/08 06:00 [pubmed]
PHST- 2020/09/15 06:00 [medline]
PHST- 2020/07/08 06:00 [entrez]
PHST- 2021/01/06 00:00 [pmc-release]
AID - 2007136117 [pii]
AID - 202007136 [pii]
AID - 10.1073/pnas.2007136117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17389-17398. doi: 
      10.1073/pnas.2007136117. Epub 2020 Jul 6.