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Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic
Paula Dietrich1, Irudayam Maria Johnson1, Shanta Alli1
1Department of Physiology, The University of Tennessee, Health Science Center, Memphis, Tennessee, United States of America.
Plos Genetics
|July 18, 2017
Summary
Huntington's Disease (HD) research shows that eliminating huntingtin (HTT) in adult mice causes behavioral issues and brain changes. This highlights potential risks of HTT silencing therapies for HD patients.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's Disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene.
- Current therapeutic strategies for HD explore silencing HTT expression.
- The essential functions of HTT in the adult brain remain largely unknown, posing risks for HTT-silencing therapies.
Purpose of the Study:
- To investigate the consequences of conditionally inactivating the mouse HD gene homologue (Htt) in the adult brain.
- To understand the role of Htt in adult brain function and pathology.
Main Methods:
- Utilized the Cre-loxP system for conditional gene inactivation of Htt in adult mice at 3, 6, and 9 months of age.
- Assessed behavioral deficits, neuropathological changes, and brain iron homeostasis.
Main Results:
- Elimination of Htt expression in adult mice led to significant behavioral deficits.
- Progressive neuropathological changes were observed, including bilateral thalamic calcification.
- Altered brain iron homeostasis was detected in Htt-inactivated mice.
Conclusions:
- Sustained suppression of Htt in the adult brain results in detrimental effects, including behavioral and neuropathological alterations.
- These findings suggest potential risks associated with HTT-silencing therapies for Huntington's Disease due to the essential role of HTT in adult brain function.
- Further research is needed to fully elucidate the consequences of HTT suppression and to develop safer therapeutic strategies for HD.
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