The study by Liu et al. indicates that microRNAs function as powerful regulators of post-transcriptional gene regulation in the adult and aging brain. The paper neatly demonstrates that when several newly identified targets of miR-34 escape regulation, late-onset brain degeneration ensues. Using the Drosophila fly as a model system, the authors could demonstrate that flies lacking miR-34 were born with no obvious defects; however, with aging these flies developed motoric dysfunction and brain degeneration.

These interesting and timely observations build on a recent body of evidence that implicates microRNAs as important molecular components of a healthy aging process.

This paper has identified some exciting and novel targets of miR-34 regulation that may be conserved. However, the targets of individual microRNAs can number in the hundreds to thousands. Indeed, this paper has identified E74A-dependent and E74A-independent pathways to disease in the absence of miR-34.

Drosophila flies expressing a polyQ disease protein (ataxin-3 polyglutamine) exhibit...  Read more

The study by Liu et al. indicates that microRNAs function as powerful regulators of post-transcriptional gene regulation in the adult and aging brain. The paper neatly demonstrates that when several newly identified targets of miR-34 escape regulation, late-onset brain degeneration ensues. Using the Drosophila fly as a model system, the authors could demonstrate that flies lacking miR-34 were born with no obvious defects; however, with aging these flies developed motoric dysfunction and brain degeneration.

These interesting and timely observations build on a recent body of evidence that implicates microRNAs as important molecular components of a healthy aging process.

This paper has identified some exciting and novel targets of miR-34 regulation that may be conserved. However, the targets of individual microRNAs can number in the hundreds to thousands. Indeed, this paper has identified E74A-dependent and E74A-independent pathways to disease in the absence of miR-34.

Drosophila flies expressing a polyQ disease protein (ataxin-3 polyglutamine) exhibit pathogenic protein inclusions. By upregulating miR-34, Liu and coworkers could demonstrate that protein inclusion formation and neurodegeneration slowed. We have recently found that miR-34b was significantly elevated in response to mHTT-Exon-1 (encoding a polyQ protein), and its blockade altered the toxicity of mHTT-Exon-1 in neuronal cell cultures (Gaughwin et al., 2011). Similar to Liu and coworkers, our data suggested that miR-34b exerts neuroprotective mechanisms in early starges of disease, but this effect is lost with disease progression.

More generally, the study highlights the true value of microRNAs as regulators of multiple co-regulated cellular processes that need to be controlled simultaneously for optimal brain aging and homeostasis. Therefore, further exploration of the biologically conserved targets of a single microRNA in biological systems that model normal brain aging will establish a diverse array of defined biochemical pathways, each with potential for therapeutic modulation. Rigorous exploration of these pathways and their relative contribution in invertebrate model systems is a powerful method to explore this further.

View all comments by Maria Björkqvist
View all comments by Philip Gaughwin

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...  Read more

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 [5]) 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.

References:
1. Agostini M, Tucci P, Killick R, Candi E, Sayan BS, et al. (2011) Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci U S A 108: 21093-21098. Abstract

2. Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, et al. (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30: 4299-4308. Abstract

3. Miñones-Moyano E, Porta S, Escaramis G, Rabionet R, Iraola S, et al. (2011) MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 20: 3067-3078. Abstract

4. Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, et al. (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease. Hum Mol Genet 20: 2225-2237. Abstract

5. Delay C, Mandemakers W, Hebert SS (2012) MicroRNAs in Alzheimer's disease. Neurobiol Dis. 2012 Jan 17. Abstract

View all comments by Sebastien S. Hebert