PMID- 23349832
OWN - NLM
STAT- MEDLINE
DCOM- 20130724
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 1
DP  - 2013
TI  - MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic 
      effects and may also target specific Huntington's disease-related mechanisms.
PG  - e54222
LID - 10.1371/journal.pone.0054222 [doi]
LID - e54222
AB  - BACKGROUND: Whereas many causes and mechanisms of neurodegenerative diseases have 
      been identified, very few therapeutic strategies have emerged in parallel. One 
      possible explanation is that successful treatment strategy may require 
      simultaneous targeting of more than one molecule of pathway. A new therapeutic 
      approach to have emerged recently is the engagement of microRNAs (miRNAs), which 
      affords the opportunity to target multiple cellular pathways simultaneously using 
      a single sequence. METHODOLOGY/PRINCIPAL FINDINGS: We identified miR-22 as a 
      potentially neuroprotective miRNA based on its predicted regulation of several 
      targets implicated in Huntington's disease (histone deacetylase 4 (HDAC4), REST 
      corepresor 1 (Rcor1) and regulator of G-protein signaling 2 (Rgs2)) and its 
      diminished expression in Huntington's and Alzheimer's disease brains. We then 
      tested the hypothesis that increasing cellular levels of miRNA-22 would achieve 
      neuroprotection in in vitro models of neurodegeneration. As predicted, 
      overexpression of miR-22 inhibited neurodegeneration in primary striatal and 
      cortical cultures exposed to a mutated human huntingtin fragment (Htt171-82Q). 
      Overexpression of miR-22 also decreased neurodegeneration in primary neuronal 
      cultures exposed to 3-nitropropionic acid (3-NP), a mitochondrial complex II/III 
      inhibitor. In addition, miR-22 improved neuronal viability in an in vitro model 
      of brain aging. The mechanisms underlying the effects of miR-22 included a 
      reduction in caspase activation, consistent with miR-22's targeting the 
      pro-apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38) 
      and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). Moreover, 
      HD-specific effects comprised not only targeting HDAC4, Rcor1 and Rgs2 mRNAs, but 
      also decreasing focal accumulation of mutant Htt-positive foci, which occurred 
      via an unknown mechanism. CONCLUSIONS: These data show that miR-22 has 
      multipartite anti-neurodegenerative activities including the inhibition of 
      apoptosis and the targeting of mRNAs implicated in the etiology of HD. These 
      results motivate additional studies to evaluate the feasibility and therapeutic 
      efficacy of manipulating miR-22 in vivo.
FAU - Jovicic, Ana
AU  - Jovicic A
AD  - Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, Vaud, 
      Switzerland.
FAU - Zaldivar Jolissaint, Julien Francisco
AU  - Zaldivar Jolissaint JF
FAU - Moser, Roger
AU  - Moser R
FAU - Silva Santos, Mariana de Fatima
AU  - Silva Santos Mde F
FAU - Luthi-Carter, Ruth
AU  - Luthi-Carter R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130117
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Co-Repressor Proteins)
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (MIRN22 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nitro Compounds)
RN  - 0 (Propionates)
RN  - 0 (RCOR1 protein, human)
RN  - 0 (RGS Proteins)
RN  - 0 (RGS2 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Repressor Proteins)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 3.5.1.98 (HDAC4 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - QY4L0FOX0D (3-nitropropionic acid)
SB  - IM
MH  - 3' Untranslated Regions/genetics
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Blotting, Western
MH  - Brain/metabolism/pathology
MH  - Cell Survival/drug effects/genetics
MH  - Cells, Cultured
MH  - Co-Repressor Proteins
MH  - Gene Expression Regulation
MH  - Genetic Predisposition to Disease/*genetics
MH  - HEK293 Cells
MH  - Histone Deacetylases/genetics
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*genetics/metabolism
MH  - Luciferases/genetics/metabolism
MH  - MicroRNAs/*genetics
MH  - Mutation
MH  - Nerve Tissue Proteins/genetics
MH  - Neurons/cytology/drug effects/metabolism
MH  - Nitro Compounds/pharmacology
MH  - Propionates/pharmacology
MH  - RGS Proteins/genetics
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Repressor Proteins/genetics
PMC - PMC3547907
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/01/26 06:00
MHDA- 2013/07/25 06:00
PMCR- 2013/01/17
CRDT- 2013/01/26 06:00
PHST- 2012/07/17 00:00 [received]
PHST- 2012/12/10 00:00 [accepted]
PHST- 2013/01/26 06:00 [entrez]
PHST- 2013/01/26 06:00 [pubmed]
PHST- 2013/07/25 06:00 [medline]
PHST- 2013/01/17 00:00 [pmc-release]
AID - PONE-D-12-21692 [pii]
AID - 10.1371/journal.pone.0054222 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(1):e54222. doi: 10.1371/journal.pone.0054222. Epub 2013 Jan 17.