Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice.
Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice.
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DOI：
10.1261/rna.044008.113
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Pillai B
中科院分区：
文献类型：
--
作者：
Roshan R;Shridhar S;Sarangdhar MA;Banik A;Chawla M;Garg M;Singh VP;Pillai B
The authors investigate the consequences of miR-29a/b misregulation in the mouse brain. They use a neurotropic peptide, derived from the rabies virus glycoprotein (RVG), for targeted delivery of an miRNA inhibitor (miR-29a/b LNA anti-miR) to neuronal cells in vivo, overcoming the blood-brain barrier, and down-regulating miR-29a/b expression in the brain. They show that the mitochondrial outer membrane protein VDAC1 is a target of this miRNA and its dysregulation is a critical feature of neuronal cell death, highlighting the protective role of miR-29 in neuronal survival. Several microRNAs have been implicated in neurogenesis, neuronal differentiation, neurodevelopment, and memory. Development of miRNA-based therapeutics, however, needs tools for effective miRNA modulation, tissue-specific delivery, and in vivo evidence of functional effects following the knockdown of miRNA. Expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and spinocerebellar ataxias. The temporal expression pattern of miR-29b during development also correlates with its protective role in neuronal survival. Here, we report the cellular and behavioral effect of in vivo, brain-specific knockdown of miR-29. We delivered specific anti-miRNAs to the mouse brain using a neurotropic peptide, thus overcoming the blood-brain-barrier and restricting the effect of knockdown to the neuronal cells. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival. The mice showed characteristic features of ataxia, including reduced step length. However, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29. In contrast, another miR-29 target, voltage-dependent anion channel1 (VDAC1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown. Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells. Our study suggests that regulation of VDAC1 expression by miR-29 is an important determinant of neuronal cell survival in the brain. Loss of miR-29 results in dysregulation of VDAC1, neuronal cell death, and an ataxic phenotype.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
10.5
作者：
Kole, Adam J.;Swahari, Vijay;Deshmukh, Mohanish
通讯作者：
Deshmukh, Mohanish
DOI：
10.1523/jneurosci.2390-08.2008
发表时间：
2008-12-31
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Packer AN;Xing Y;Harper SQ;Jones L;Davidson BL
通讯作者：
Davidson BL
影响因子：
56.9
作者：
Kim, Jongpil;Inoue, Keiichi;Abeliovich, Asa
通讯作者：
Abeliovich, Asa
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart