From microRNA target validation to therapy : lessons learned from studies on BDNF

During the past decade, the identification of microRNA (miR) targets has become common laboratory practice, and various strategies are now used to detect interactions between miRs and their mRNA targets. However, the current lack of a standardized identification process often leads to incomplete and/or conflicting results. Here, we review the problems most commonly encountered when verifying miR-mRNA interactions, and we propose a workflow for future studies. To illustrate the challenges faced when validating a miR target, we discuss studies in which the regulation of brain-derived neurotrophic factor by miRs was investigated, and we highlight several controversies that emerged from these studies. Finally, we discuss the therapeutic use of miR inhibitors, and we discuss several questions that should be addressed before proceeding to preclinical testing.Peer reviewe

A Coalgebraic View of Infinite Trees and Iteration

AbstractThe algebra of infinite trees is, as proved by C. Elgot, completely iterative, i.e., all ideal recursive equations are uniquely solvable. This is proved here to be a general coalgebraic phenomenon: let H be an endofunctor such that for every object X a final coalgebra, TX, of H(_) + X exists. Then TX is an object-part of a monad which is completely iterative. Moreover, a similar contruction of a “completely iterative monoid” is possible in every monoidal category satisfying mild side conditions

Short-term Preoperative Dietary Restriction Is Neuroprotective in a Rat Focal Stroke Model

Peer reviewe

GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

Peer reviewe

Molecular mechanisms of fasting-induced neuroprotection.

<p>(A) Experimental timeline indicating dietary treatments and experimental endpoints relative to tMCAO on day 0. (B) Relative expression of the indicated genes in the striatum of <i>ad libitum</i> fed (AL, n = 6) and fasted (FA, n = 5) rats at baseline, measured by qPCR and expressed relative to the AL group. (C) Relative expression of selected genes in AL (n = 5) and FA (n = 6) rats 24 hours after tMCAO in the unlesioned left (L) and lesioned right (R) striata, measured by qPCR and expressed relative to the unlesioned AL group; *p<0.05, **p<0.01, ***p<0.001, 1-way ANOVA. (D) Serum CXCL1 levels in AL (n = 12) and FA (n = 12) rats at baseline; **p = 0.0021, Student's <i>t</i>-test.</p

Preoperative 3-day water-only fasting is neuroprotective against stroke.

<p>(A) Experimental timeline indicating periods of <i>ad libitum</i> feeding and fasting relative to the onset of tMCAO on day 0. AL, <i>ad libitum</i> fed (n = 11); FA, fasted (n = 14). (B) Average body weights prior to and after tMCAO; F_{8, 23} = 17.69, ***p<0.0001, 2-way ANOVA. (C) Blood glucose levels on the indicated days prior to and after tMCAO; F_{2, 23} = 14.09, ***p<0.0001, 2-way ANOVA. (D) Body temperature before tMCAO and 1 hour after reperfusion; ***/^###p<0.001, Student's <i>t</i>-test. (E) Infarction volumes at d7 after tMCAO; *p = 0.0215, Student's <i>t</i>-test. (F) Representative MRI images of the lesioned brain sections with green lines surrounding the lesion.</p

Protein-free DR is neuroprotective against stroke.

<p>(A) Experimental timeline indicating periods of <i>ad libitum</i> access to a complete diet (AL, n = 15) or restricted access to a protein-free diet (PF, n = 14) relative to the onset of tMCAO on day 0. (B) TTC-stained brain sections showing infarct size (white area). (C) Total infarction volume on d2 after tMCAO; *p = 0.0396, Student's <i>t-</i>test. (D) Average maximal infarction area from the slice with the largest infarction area per animal; *p = 0.0320, Student's <i>t-</i>test. (E) Biased body swing activity in 20 trials; **p = 0.0016, Mann-Whitney <i>U</i>-test. (F) Behavioral performance assessed by modified Bederson's score; *p = 0.0396, Mann-Whitney <i>U</i>-test.</p

Plasma cytokine levels (pg/mL) 4 hours after reperfusion in rats fed <i>ad libitum</i> (AL) or fasted for 3 days (FA) prior to tMCAO; IFN, interferon; IL, interleukin, CXCL1, C-X-C motif ligand 1; TNF, tumor necrosis factor.

<p>Plasma cytokine levels (pg/mL) 4 hours after reperfusion in rats fed <i>ad libitum</i> (AL) or fasted for 3 days (FA) prior to tMCAO; IFN, interferon; IL, interleukin, CXCL1, C-X-C motif ligand 1; TNF, tumor necrosis factor.</p

GDNF is not required for catecholaminergic neuron survival in vivo.

Glial cell line-derived neurotrophic factor (GDNF) has been tested in clinical trials to treat Parkinson’s disease with promising but variable results. Improvement of therapeutic effectiveness requires solid understanding of the physiological role of GDNF in the maintenance of the adult brain catecholamine system. However, existing data on this issue is contradictory. Here we show with three complementary approaches that, independent of the time of reduction, Gdnf is not required for maintenance of catecholaminergic neurons in adult mice

Correction: GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function.

[This corrects the article DOI: 10.1371/journal.pgen.1005710.]