PMID- 30961637
OWN - NLM
STAT- MEDLINE
DCOM- 20190731
LR  - 20211204
IS  - 1756-6606 (Electronic)
IS  - 1756-6606 (Linking)
VI  - 12
IP  - 1
DP  - 2019 Apr 8
TI  - Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to 
      improved Huntington's pathology in zQ175 mice.
PG  - 35
LID - 10.1186/s13041-019-0456-1 [doi]
LID - 35
AB  - Huntington's disease (HD) is a neurodegenerative disorder caused by a genetic 
      abnormality in the huntingtin gene that leads to a polyglutamine repeat expansion 
      of the huntingtin protein. The cleaved polyglutamine expansion of mutant 
      huntingtin (mHTT) protein can form aggregates strongly correlated with HD 
      progression. We have previously shown that the inhibition of mGluR5 using CTEP, a 
      selective negative allosteric mGluR5 modulator, can delay disease progression and 
      reduce in mHTT aggregates in the zQ175 mouse model of HD. This was paralleled by 
      enhanced catalytic activity of Unc-51-like kinase 1 (ULK1), a kinase modulated by 
      mammalian target of rapamycin (mTOR) and key regulator of autophagy initiation. 
      In the present study, we show that CTEP can correct aberrant phosphoinositide 
      3-kinase (PI3K)/Akt/mTOR signaling detected in zQ175 mice that may underlie the 
      enhanced ULK1 activity and activation of autophagy. We also show that CTEP can 
      facilitate cAMP response element-binding protein (CREB)-mediated expression of 
      brain-derived neurotrophic factor (BDNF) to foster neuronal survival and reduce 
      apoptosis. Taken together, our findings provide the molecular evidence for how 
      targeting mGluR5 using a well-tolerated selective NAM can mitigate two critical 
      mechanisms of neurodegeneration, autophagy and apoptosis.
FAU - Abd-Elrahman, Khaled S
AU  - Abd-Elrahman KS
AD  - University of Ottawa Brain and Mind Institute, University of Ottawa, 451 Smyth 
      Road, Ottawa, Ontario, K1H 8M5, Canada.
AD  - Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth 
      Road, Ottawa, Ontario, K1H 8M5, Canada.
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria 
      University, Alexandria, 21521, Egypt.
FAU - Ferguson, Stephen S G
AU  - Ferguson SSG
AUID- ORCID: 0000-0002-0887-7312
AD  - University of Ottawa Brain and Mind Institute, University of Ottawa, 451 Smyth 
      Road, Ottawa, Ontario, K1H 8M5, Canada. sferguso@uottawa.ca.
AD  - Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth 
      Road, Ottawa, Ontario, K1H 8M5, Canada. sferguso@uottawa.ca.
LA  - eng
GR  - MOP 119437/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190408
PL  - England
TA  - Mol Brain
JT  - Molecular brain
JID - 101468876
RN  - 0 
      (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Imidazoles)
RN  - 0 (Proto-Oncogene Proteins c-fos)
RN  - 0 (Pyridines)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
MH  - Allosteric Regulation
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Huntington Disease/*metabolism/*pathology
MH  - Imidazoles/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Models, Biological
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-fos/metabolism
MH  - Pyridines/pharmacology
MH  - Receptor, Metabotropic Glutamate 5/*antagonists & inhibitors/metabolism
MH  - *Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC6454676
OTO - NOTNLM
OT  - BDNF
OT  - CTEP
OT  - Huntington's disease
OT  - ULK1
OT  - autophagy
OT  - mGluR5
OT  - mHTT
OT  - mTOR
OT  - zQ175
COIS- ETHICS APPROVAL: All animal experiments were conducted in accordance with 
      University of Ottawa animal care committees. CONSENT FOR PUBLICATION: Not 
      applicable. COMPETING INTERESTS: The authors declare that they have no competing 
      interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to 
      jurisdictional claims in published maps and institutional affiliations.
EDAT- 2019/04/10 06:00
MHDA- 2019/08/01 06:00
PMCR- 2019/04/08
CRDT- 2019/04/10 06:00
PHST- 2019/03/04 00:00 [received]
PHST- 2019/03/29 00:00 [accepted]
PHST- 2019/04/10 06:00 [entrez]
PHST- 2019/04/10 06:00 [pubmed]
PHST- 2019/08/01 06:00 [medline]
PHST- 2019/04/08 00:00 [pmc-release]
AID - 10.1186/s13041-019-0456-1 [pii]
AID - 456 [pii]
AID - 10.1186/s13041-019-0456-1 [doi]
PST - epublish
SO  - Mol Brain. 2019 Apr 8;12(1):35. doi: 10.1186/s13041-019-0456-1.