MicroRNAs: novel therapeutic targets in neurodegenerative diseases

Roshan, Reema; Ghosh, Tanay; Scaria, Vinod; Pillai, Beena

doi:10.1016/j.drudis.2009.09.009

Cited by 79 publications

(66 citation statements)

References 53 publications

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“…Multidisciplinary research has explored various approaches for preventing and/or delaying the onset of latelife dementia (Larson, 2010). There is a great interest in novel therapeutic approaches to treat dementia, one of which in early development is gene therapy (Roshan et al, 2009). Our findings suggest that miR-195 might be a candidate for dementiatargeting gene therapy in the future.…”

Section: Limitations and Prospectsmentioning

confidence: 99%

MicroRNA-195Protects Against Dementia Induced by Chronic Brain Hypoperfusion via Its Anti-Amyloidogenic Effect in Rats

et al. 2013

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Previous studies have demonstrated that chronic brain hypoperfusion (CBH) causes A␤ aggregation by upregulating expression of amyloid precursor protein (APP) and ␤-site APP cleaving enzyme 1 (BACE1) protein, which is accompanied by cognitive impairment, but the mechanisms are not fully understood. In this study, we evaluated the effect of microRNA on memory impairment in rats induced by CBH. We show here that CBH generated by bilateral common carotid artery occlusion (2VO) significantly decreased the learning and memory ability in rats, as assessed by Morris water maze, and upregulated expression of APP and BACE1 proteins in the hippocampus and cortex of rats, as evaluated by Western blot and immunofluorescence. In reciprocal, qRT-PCR analysis showed that microRNA-195 (miR-195) was downregulated in both the hippocampus and cortex of rats following CBH, and in the plasma of dementia patients. APP and BACE1 proteins were downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation or miR-masks, indicating that APP and BACE1 are two potential targets for miR-195. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) elicited dementia in rats, whereas overexpression of miR-195 using lenti-pre-miR-195 reduced dementia vulnerability triggered by 2VO. Additionally, chromatin immunoprecipitation analysis showed that NFB was bound to the promoter region of miR-195 and inhibited its expression. We conclude that miR-195 may play a key role in determining dementia susceptibility in 2VO rats by regulating APP and BACE1 expression at the post-transcriptional level, and exogenous complement of miR-195 may be a potentially valuable anti-dementia approach.

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Section: Limitations and Prospectsmentioning

confidence: 99%

MicroRNA-195Protects Against Dementia Induced by Chronic Brain Hypoperfusion via Its Anti-Amyloidogenic Effect in Rats

et al. 2013

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“…Apoptosis is a necessary aspect of neuronal development and the underlying mechanism by which neurodegenerative diseases are manifested. The appropriate expression of regulatory elements such as miRNA maintains the balance between survival and apoptosis (Kent and Mendell 2006;Roshan et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Roshan

Shridhar

Sarangdhar

et al. 2014

RNA

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124

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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, voltagedependent 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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“…This is the first study to fully characterize the transcriptome of the hypothalamus in 24-h fasting, compared to the ad lib fed animals. Given the previous published studies showing differential regulation of microRNAs in brain, adipose and other tissues conditions such as cancer or obesity, it was surprising to find so few differentially expressed microRNAs via microarray analysis and none that could be confirmed by further QPCR analysis (Fassan et al 2011;Martinelli et al 2010;McNeill and Van Vactor 2012;Roshan et al 2009;Sun et al 2011;Takanabe et al 2008). Although current database information suggests that there are only 105 microRNAs expressed in the midbrain above the detection threshold (http://www.microrna.org), we detected 536 microRNAs using the Affymetrix microarrays.…”

Section: Discussionmentioning

confidence: 99%

“…microRNAs have been reported to be differentially expressed in several brain disorders, including neuronal cancers, and neurodegeneration (Fassan et al 2011;Roshan et al 2009). There are also studies that demonstrate a role for microRNAs in more normal physiological processes, such as learning, synaptic plasticity and neuroadaptation (McNeill and Van Vactor 2012).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the hypothalamic transcriptome in response to food deprivation reveals global changes in long noncoding RNA, and cell cycle response genes

et al. 2015

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The hypothalamus integrates energy balance information from the periphery using different neuronal subtypes within each of the hypothalamic areas. However, the effects of prandial state on global mRNA, microRNA and long noncoding (lnc) RNA expression within the whole hypothalamus are largely unknown. In this study, mice were given either a 24-h fast, or ad libitum access to food. RNA samples were analyzed by microarray, and then a subset was confirmed using quantitative real-time PCR (QPCR). A total of 540 mRNAs were either up-or downregulated with food deprivation. Since gene ontology enrichment analyses identified several categories of mRNAs related to cell cycle processes, ten cell-cycle-related genes were further analyzed using QPCR with six confirmed to be significantly up-regulated and one downregulated in response to 24-h fasting. While 22 independent microRNAs were differentially expressed by microarray, secondary analysis by QPCR failed to confirm significant changes with fasting. There were 622 lncRNAs identified as differentially expressed, and of three tested by QPCR, two were confirmed. Overall, this is the first time that expression of hypothalamic lncRNAs has been shown to be responsive to food deprivation. In addition, this study is the first to identify a list of lncRNAs with high expression in RNA extracted from hypothalamus. Individual contributions from specific miRNA, lncRNA and mRNAs to the food deprivation response can now be further studied at the physiological and biochemical levels.

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MicroRNAs: novel therapeutic targets in neurodegenerative diseases

Cited by 79 publications

References 53 publications

MicroRNA-195Protects Against Dementia Induced by Chronic Brain Hypoperfusion via Its Anti-Amyloidogenic Effect in Rats

MicroRNA-195Protects Against Dementia Induced by Chronic Brain Hypoperfusion via Its Anti-Amyloidogenic Effect in Rats

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Characterization of the hypothalamic transcriptome in response to food deprivation reveals global changes in long noncoding RNA, and cell cycle response genes

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