Cause or Effect: Misregulation of microRNA Pathways in Neurodegeneration

Department of Neurology, University of Massachusetts Medical School Worcester, MA, USA.
Frontiers in Neuroscience (Impact Factor: 3.66). 04/2012; 6:48. DOI: 10.3389/fnins.2012.00048
Source: PubMed


During normal aging or neurodegenerative diseases, neuronal survival and function depend on protein homeostasis, which is regulated by multiple mechanisms, including the microRNA (miRNA) pathway. In different cells types, the absence of Dicer, a key miRNA processing enzyme, leads to neurodegeneration through cell-autonomous and non-cell-autonomous mechanisms. Loss of certain miRNAs also causes neurodegeneration in some model organisms. On the other hand, miRNA expression is misregulated in patients with different neurodegenerative diseases. Thus, the miRNA pathway appears to be essential in the pathogenesis of several age-dependent neurodegenerative conditions; however, our understanding of the underlying mechanism remains rudimentary. The precise causal relationships between specific miRNAs and neurodegeneration in humans need to be further investigated.

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    • "Recently miRNAs have been identified as crucial regulators of immune cell development and function. Deregulated miRNAs contribute to the development of various diseases, for example, cancer, cardiovascular, or neurological diseases (Bonauer et al., 2010; Gascon and Gao, 2012; Thum, 2012). Neurodegeneration is characterized by neuronal loss of specific neuronal circuits associated with cognitive and motor functions and by changes in miRNA levels in the nervous tissue and in the periphery. "
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    ABSTRACT: The etiology of neuroinflammation is complex and comprises multifactorial, involving both genetic and environmental factors during which diverse genetic and epigenetic modulations are implicated. Curcumin (Cur), and valproic acid (VPA), histone deacetylase 1 inhibitor, have neuroprotective effects. The present study was designed with an aim to investigate the ability of co-treatment of both compounds (Cur or VPA (200mg/kg) for four weeks to augment neuroprotection and enhance brain recovery from intra-peritoneal (IP) injection of (250 µg/kg) lipopolysaccharide (LPS)-stimulated neuroinflammatory condition on rat brain cortex. Cortex activation and the effects of combined treatment and production of proinflammatory mediators, COX-2, APE1 and nitric oxide/iNOS were investigated. Neuroinflammation development was assessed by histological analyses and by investigating associated indices (BACE1, APP, PSEN-1 and PSEN-2). Furthermore we measured the expression profile of let-7 miRNAs members a, b, c, e and f in all groups, a highly abundant regulator of gene expression in the CNS. Protein and mRNA levels of neuroinflammation markers COX-2, BACE1, APP and iNOS were also attenuated by combined therapy. On the other hand, assessment of the indicated five let-7 members, showed distinct expression profile pattern in the different groups. Let-7 a, b and c disappeared in the induced group, an effect that was partially suppressed by co-addition of either Cur or VPA. These data suggest that the combined treatment induced significantly the expression of the five members when compared to rats treated with Cur or VPA only as well as to self-recovery group, which indicates a possible benefit from the synergistic effect of Cur-VPA combination as therapeutic agents for neuroinflammation and its associated disorders. The mechanism elucidated here highlights the particular drug-induced expression profile of let-7 family as new targets for future pharmacological development.
    Frontiers in Cellular Neuroscience 10/2014; 8:337. DOI:10.3389/fncel.2014.00337 · 4.29 Impact Factor
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    • "Moreover, it was recently proposed that specific RBPs or miR- NAs might be secreted from stressed motoneurons to stimulate defence mechanisms in astrocytes or endothelial cells (Aparicio-Erriu and Prehn, 2012; Gascon and Gao, 2012). This indicates that perturbed homeostasis of RBPs or miR- NAs, and the consequent changes in RNA metabolism may play a central role in neurodegenerative processes (Aparicio- Erriu and Prehn, 2012; Gascon and Gao, 2012; Kapeli and Yeo, 2012). Taken together, we feel that the present collection of reviews on the mRNA life cycle in normal brain function and malfunction provides a timely update by leading researchers to reflect recent developments in key technologies , and summarizes the current understanding and future directions for the studies of mRNA metabolism in the brain. "

    Frontiers in Neuroscience 10/2013; 7(7):192. DOI:10.3389/fnins.2013.00192 · 3.66 Impact Factor
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    • "MiRNAs are small noncoding RNAs that regulate gene expression post-transcriptionally by degrading their target mRNAs or repressing their translation [19], [20]. Although potential involvement of miRNAs in neurodegeneration has been increasingly appreciated, information about their regulation and function in diseased human neurons remains scarce [21]. "
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    ABSTRACT: Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts.
    PLoS ONE 10/2013; 8(10):e76055. DOI:10.1371/journal.pone.0076055 · 3.23 Impact Factor
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