Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease.

Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease.

Publication date: Nov 06, 2019

Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.

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Irvine, E.E., Katsouri, L., Plattner, F., Al-Qassab, H., Al-Nackkash, R., Bates, G.P., and Withers, D.J. Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease. 06757. 2019 Sci Rep (9):1.

Concepts Keywords
Autosomal Dominant Trinucleotide repeat disorder
Brain ATM serine/threonine kinase
Cognitive Ageing
Deregulation Sirolimus
Gene P70-S6 Kinase 1
Genetic Deletion Huntingtin
Huntingtin MTOR
Huntington Signal transduction
Kinase Huntington’s disease
Knockout Branches of biology
Molecule Behavioural cognitive symptoms
MTOR
Neurodegenerative Disorder
Phenotypes
Phenotypic
Rapamycin
S6K1
S6k1
Sci
Trinucleotide Repeats

Semantics

Type Source Name
gene UNIPROT SLC6A4
gene UNIPROT ADCY10
pathway BSID Glucose metabolism
gene UNIPROT DELE1
disease MESH dif
drug DRUGBANK Isoxaflutole
disease MESH heterozygote
drug DRUGBANK Dextrose unspecified form
gene UNIPROT GKN2
gene UNIPROT GOPC
gene UNIPROT DEPP1
pathway BSID Aging
disease MESH aging
disease MESH tremor
gene UNIPROT FANCC
disease MESH growth
gene UNIPROT INS
disease MESH multi
gene UNIPROT CCAR1
disease MESH weight loss
disease MESH cognitive decline
disease MESH death
drug DRUGBANK Coenzyme M
drug DRUGBANK Sirolimus
gene UNIPROT MTOR
gene UNIPROT HTT
disease MESH neurodegenerative disorder
gene UNIPROT RPS6KB1
drug DRUGBANK Everolimus
gene UNIPROT PDXP
disease MESH atrophy
disease DOID Dementia
disease MESH Dementia

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