Publication Date:
2012-02-22
Description:
Human neurodegenerative diseases have the temporal hallmark of afflicting the elderly population. Ageing is one of the most prominent factors to influence disease onset and progression, yet little is known about the molecular pathways that connect these processes. To understand this connection it is necessary to identify the pathways that functionally integrate ageing, chronic maintenance of the brain and modulation of neurodegenerative disease. MicroRNAs (miRNA) are emerging as critical factors in gene regulation during development; however, their role in adult-onset, age-associated processes is only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration. Fly mir-34 expression exhibits adult-onset, brain-enriched and age-modulated characteristics. Whereas mir-34 loss triggers a gene profile of accelerated brain ageing, late-onset brain degeneration and a catastrophic decline in survival, mir-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326599/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326599/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Nan -- Landreh, Michael -- Cao, Kajia -- Abe, Masashi -- Hendriks, Gert-Jan -- Kennerdell, Jason R -- Zhu, Yongqing -- Wang, Li-San -- Bonini, Nancy M -- AG010124/AG/NIA NIH HHS/ -- R01 NS043578/NS/NINDS NIH HHS/ -- R01 NS043578-05/NS/NINDS NIH HHS/ -- R01-NS043578/NS/NINDS NIH HHS/ -- RC2 AG036528/AG/NIA NIH HHS/ -- RC2 AG036528-01/AG/NIA NIH HHS/ -- RC2-AG036528-01/AG/NIA NIH HHS/ -- T32 AG000255/AG/NIA NIH HHS/ -- T32 AG000255-02/AG/NIA NIH HHS/ -- T32 AG00255/AG/NIA NIH HHS/ -- U01 AG032984/AG/NIA NIH HHS/ -- U01 AG032984-02/AG/NIA NIH HHS/ -- U01-AG-032984-02/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 15;482(7386):519-23. doi: 10.1038/nature10810.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343898" target="_blank"〉PubMed〈/a〉
Keywords:
Aging/*genetics
;
Animals
;
Brain/metabolism/pathology
;
*Disease Models, Animal
;
Down-Regulation
;
Drosophila Proteins/biosynthesis/genetics
;
Drosophila melanogaster/*genetics/*physiology
;
Female
;
Gene Expression Regulation/*genetics
;
Hot Temperature
;
Humans
;
Longevity/genetics
;
Male
;
MicroRNAs/*genetics
;
Mutation
;
Neurodegenerative Diseases/*genetics/pathology
;
Protein Biosynthesis
;
RNA, Messenger/analysis/genetics
;
Survival Analysis
;
Time Factors
;
Transcription Factors/biosynthesis/genetics
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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