Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington’s pathology in zQ175 mice.

Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington’s pathology in zQ175 mice.

Publication date: Apr 08, 2019

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.

Abd-Elrahman, K.S. and Ferguson, S.S.G. Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington’s pathology in zQ175 mice. 06441. 2019 Mol Brain (12):1.

Concepts Keywords
Akt Apoptosis
Allosteric Brain-derived neurotrophic factor
Apoptosis Protein kinase B
Autophagy Autophagy
BDNF Huntingtin
Blockade ULK1
CAMP Oncology
Catalytic Protein kinases
CREB MTOR
Genetic Signal transduction
Huntingtin Branches of biology
Huntingtin Protein HD neurodegenerative disorder
Huntington
Kinase
MGluR5
Mice
MTOR
Mutant
NAM
Neurodegeneration
Neurodegenerative Disorder
Pathology
Phosphoinositide
PI3K
Polyglutamine Expansion
Rapamycin

Semantics

Type Source Name
gene UNIPROT STAC3
pathway BSID Apoptosis
gene UNIPROT BDNF
gene UNIPROT CHAMP1
gene UNIPROT CAMP
gene UNIPROT MTOR
gene UNIPROT CREB1
gene UNIPROT GRM5
disease MESH neurodegenerative disorder
disease MESH disease progression
gene UNIPROT ULK1
drug DRUGBANK Sirolimus
gene UNIPROT PIK3CA
gene UNIPROT PIK3CD
gene UNIPROT PIK3CB
gene UNIPROT PIK3CG
gene UNIPROT AKT1
drug DRUGBANK Cyclic Adenosine Monophosphate

Original Article

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