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Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model.

ABSTRACT: A polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntington's disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are viable with no obvious developmental defects. Instead, dhtt is required for maintaining the mobility and long-term survival of adult animals, and for modulating axonal terminal complexity in the adult brain. Furthermore, removing endogenous dhtt significantly accelerates the neurodegenerative phenotype associated with a Drosophila model of polyglutamine Htt toxicity (HD-Q93), providing in vivo evidence that disrupting the normal function of Htt might contribute to HD pathogenesis.

SUBMITTER: Zhang S

PROVIDER: S-EPMC2675792 | biostudies-literature | 2009 May-Jun

REPOSITORIES: biostudies-literature

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Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model.

Zhang Sheng S Feany Mel B MB Saraswati Sudipta S Littleton J Troy JT Perrimon Norbert N

Disease models & mechanisms 20090406 5-6

A polyglutamine expansion in the huntingtin (HTT) gene causes neurodegeneration in Huntington's disease (HD), but the in vivo function of the native protein (Htt) is largely unknown. Numerous biochemical and in vitro studies have suggested a role for Htt in neuronal development, synaptic function and axonal trafficking. To test these models, we generated a null mutant in the putative Drosophila HTT homolog (htt, hereafter referred to asdhtt) and, surprisingly, found that dhtt mutant animals are ...[more]

PMID: 19380309

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Project description:ImportanceDuring an ongoing longitudinal cohort study, a casino opening created a natural cash transfer experiment. Some participating families received income supplements, and others did not. The children in this study are now adults.ObjectiveTo assess the long-term outcomes of family income supplements received in childhood.Design, setting, and participantsThis community-representative longitudinal cohort study set in western North Carolina assessed 1266 participants aged 9, 11, and 13 years at intake up to 11 times up to age 30 years from January 1993 to December 2015. Data were analyzed from January to December 2021.ExposuresIn 1996, a southeastern American Indian tribe implemented a cash transfer program of approximately $5000 annually per person for tribal members. Participants were compared on whether their family ever received the cash transfers (American Indian vs non-American Indian), the duration of the transfers, and annual amount based on the number of parents.Main outcomes and measuresParticipants were followed up at ages 25 and 30 years to assess mental health symptoms, substance use symptoms, and functional outcomes (physical health, risky or illegal behaviors, and financial and social functioning).ResultsOf 1266 included participants, 320 (25.3%) were American Indian and 581 (49.7%) were female. Participants whose families received cash transfers during childhood reported fewer anxiety symptoms (relative risk [RR], 0.33; 95% CI, 0.25-0.44), depressive symptoms (RR, 0.51; 95% CI, 0.42-0.62), and cannabis symptoms (RR, 0.47; 95% CI, 0.27-0.82). They also reported improved physical health (RR, 0.66; 95% CI, 0.55-0.80) and financial functioning (RR, 0.78; 95% CI, 0.67-0.89) and fewer risky or illegal behaviors (RR, 0.57; 95% CI, 0.46-0.72) compared with those who did not receive the cash transfer. This pattern was supported by a series of heterogeneity analyses in which children whose families received the transfers for the longest duration and whose families received the largest transfer (due to having multiple American Indian parents) had the lowest levels of symptoms and the highest levels of functioning.Conclusions and relevanceIn this natural experiment, a family cash transfer in childhood was associated with positive adult functioning 20 years later. The findings support programs like the child tax credit or universal basic income that provide cash directly to families with children.

Dataset Information

Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model.

Publications

Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington's disease model.

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