Liu N, Landreh M, Cao K, Abe M, Hendriks GJ, Kennerdell JR, Zhu Y, Wang LS, Bonini NM.
The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila.
Nature. 2012 Feb 23;482(7386):519-23.
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In the past months, much attention has been turned towards the involvement of miR-34 in brain health and disease. Here, the Bonini group provides compelling evidence that miR-34 is important for normal brain aging, with potential implications in neurodegenerative disease. The authors identified miR-34 to be selectively upregulated in aged (30- and 60-day-old) flies. They showed that adult miR-34 mutant (knockout) flies displayed decreased lifespan, behavioral changes, and abnormal vacuolization, indicative of loss of brain integrity. Importantly, rescue experiments reversed these defects, at least for the most part. They further identified Eip74EF, a component of steroid hormone signaling pathways, as a potential miR-34 effector gene. Interestingly, miR-34 controlled mainly Eip74EF protein, but not messenger RNA, levels. Notably, gain-of-function experiments demonstrated that miR-34 rescued ataxin-3 polyglutamine (SCA3trQ78)-induced degeneration. This effect seemed independent of Eip74EF expression modulation, which opens the door to additional miR-34 targets involved in disease conditions. Finally, the authors showed that miR-34 overexpression alone could extend median lifespan. In sum, this study offers a comprehensive new look into the role specific brain-expressed miRNAs in both physiological and pathological conditions.
This study also has important implications for other miRNA-based studies. Indeed, changes in miR-34 have been documented in Alzheimer’s disease brain (specifically in hippocampus) (1,2), Parkinson’s disease brain (3), and Huntington’s disease plasma (4). Moreover, experiments performed in mice suggest that miR-34 is equally involved in aging and memory formation (2).
While Drosophila remains a powerful system to study miRNAs in neurodegenerative disorders, it should be noticed that not all miRNAs are conserved in humans. For instance, “AD-related” miRNAs miR-29, miR-107, miR-15, and miR-181 (reviewed in ) are not expressed in Drosophila (or C. elegans). Therefore, the use of additional models, such as mice, will most likely be necessary to fully grasp the functions of miRNAs in the adult mammalian brain.
Agostini M, Tucci P, Killick R, Candi E, Sayan BS, Rivetti di Val Cervo P, Nicotera P, McKeon F, Knight RA, Mak TW, Melino G.
Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets.
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21093-8.
Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, Farinelli L, Delalle I, Schmitt A, Falkai P, Bahari-Javan S, Burkhardt S, Sananbenesi F, Fischer A.
microRNA-34c is a novel target to treat dementias.
EMBO J. 2011 Oct 19;30(20):4299-308.
Miñones-Moyano E, Porta S, Escaramís G, Rabionet R, Iraola S, Kagerbauer B, Espinosa-Parrilla Y, Ferrer I, Estivill X, Martí E.
MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function.
Hum Mol Genet. 2011 Aug 1;20(15):3067-78.
Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, Björkqvist M.
Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease.
Hum Mol Genet. 2011 Jun 1;20(11):2225-37. Epub 2011 Mar 19
Delay C, Mandemakers W, Hébert SS.
MicroRNAs in Alzheimer's disease.
Neurobiol Dis. 2012 May;46(2):285-90.