Journal article
Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy
Annals of neurology, Vol.96(5), pp.1006-1019
10/22/2024
DOI: 10.1002/ana.27046
PMCID: PMC11496017
PMID: 39115048
Appears in UI Libraries Support Open Access
Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging-related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years-to-onset paradigm in a unique sample of children and young adults at risk for HD.OBJECTIVEHuntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging-related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years-to-onset paradigm in a unique sample of children and young adults at risk for HD.Cognitive, behavioral, motor, and brain structural measures from premanifest gene-expanded (n = 79) and gene nonexpanded (n = 112) participants (6-21 years) in the Kids-HD study were examined. All measures in the gene-expanded group were modeled using a mixed-effects regression approach to assess years-to-onset-based changes while controlling for normal growth. Simultaneously, structure-function associations were also examined.METHODSCognitive, behavioral, motor, and brain structural measures from premanifest gene-expanded (n = 79) and gene nonexpanded (n = 112) participants (6-21 years) in the Kids-HD study were examined. All measures in the gene-expanded group were modeled using a mixed-effects regression approach to assess years-to-onset-based changes while controlling for normal growth. Simultaneously, structure-function associations were also examined.Decades from motor onset, gene-expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.RESULTSDecades from motor onset, gene-expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.Mutant HTT may drive the development of a larger than normal brain that subserves superior early-life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024.INTERPRETATIONMutant HTT may drive the development of a larger than normal brain that subserves superior early-life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024.
Details
- Title: Subtitle
- Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy
- Creators
- Mohit NeemaJordan L Schultz - University of IowaDouglas R Langbehn - University of IowaAmy L Conrad - University of IowaEric A Epping - University of IowaVincent A Magnotta - University of IowaPeggy C Nopoulos
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.96(5), pp.1006-1019
- DOI
- 10.1002/ana.27046
- PMID
- 39115048
- PMCID
- PMC11496017
- NLM abbreviation
- Ann Neurol
- ISSN
- 1531-8249
- eISSN
- 1531-8249
- Publisher
- Wiley
- Grant note
- National Institute of Neurological Disorders and Stroke: R01 NS055903 CHDI Foundation: 071108 National Institutes of Health: 1S10OD025025-01
The authors thank the participants of the Kids-HD study and their family members who supported their participation. The authors acknowledge Eric Axelson for his technical assistance in MRI processing, and thank Sonia Slevinski for her long-term administrative commitment and her assistance in subject assessment. The Kids-HD study was funded by the National Institute of Neurological Disorders and Stroke (R01 NS055903) and the CHDI Foundation (071108). The MRI equipment used in this study was funded by the National Institutes of Health (1S10OD025025-01).
- Language
- English
- Electronic publication date
- 08/08/2024
- Date published
- 10/22/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Psychiatry; Pediatric Psychology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Pharmacy Practice and Science
- Record Identifier
- 9984696759502771
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