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Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy.
Neema, Mohit; Schultz, Jordan L; Langbehn, Douglas R; Conrad, Amy L; Epping, Eric A; Magnotta, Vincent A; Nopoulos, Peggy C.
Afiliación
  • Neema M; Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Schultz JL; Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Langbehn DR; Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Conrad AL; Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Epping EA; Stead Family Department of Pediatrics, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Magnotta VA; Department of Psychiatry, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
  • Nopoulos PC; Department of Radiology, Carver College of Medicine at the University of Iowa, Iowa City, IA, USA.
Ann Neurol ; 2024 Aug 08.
Article en En | MEDLINE | ID: mdl-39115048
ABSTRACT

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

INTERPRETATION:

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Ann Neurol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Ann Neurol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos