Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat

International audienceThis study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1-receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects

Mecanismes de synthese des nucleotides pyrimidiques myocardiques a partir de la cytidine

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

La contraception non hormonale

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Physiologie de la reproduction chez la femme (traitements hormonaux associés et conseils à l'officine)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Le trouble déficitaire d'attention chez l'adulte, symptomes et traitement

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Insuffisance cardiaque et bêtabloquants (le Carvedilol Kredex )

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Deséquilibre émotionnel et depression (l'usage des antidepresseurs en France et leur intérêt thérapeutique)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Neurophysiologie de la mélatonine et ses utilisations thérapeutiques

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

TP53INP1 exerts neuroprotection under ageing and Parkinson’s disease-related stress condition

International audienceTP53INP1 is a stress-induced protein, which acts as a dual positive regulator of transcription and of autophagy and whose deficiency has been linked with cancer and metabolic syndrome. Here, we addressed the unexplored role of TP53INP1 and of its Drosophila homolog dDOR in the maintenance of neuronal homeostasis under chronic stress, focusing on dopamine (DA) neurons under normal ageing-and Parkinson's disease (PD)-related context. Trp53inp1 −/− mice displayed additional loss of DA neurons in the substantia nigra compared to wild-type (WT) mice, both with ageing and in a PD model based on targeted overexpression of α-synuclein. Nigral Trp53inp1 expression of WT mice was not significantly modified with ageing but was markedly increased in the PD model. Trp53inp2 expression showed similar evolution and did not differ between WT and Trp53inp1 −/− mice. In Drosophila, pan-neuronal dDOR overexpression improved survival under paraquat exposure and mitigated the progressive locomotor decline and the loss of DA neurons caused by the human α-synuclein A30P variant. dDOR overexpression in DA neurons also rescued the locomotor deficit in flies with RNAi-induced downregulation of dPINK1 or dParkin. Live imaging, confocal and electron microscopy in fat bodies, neurons, and indirect flight muscles showed that dDOR acts as a positive regulator of basal autophagy and mitophagy independently of the PINK1-mediated pathway. Analyses in a mammalian cell model confirmed that modulating TP53INP1 levels does not impact mitochondrial stress-induced PINK1/Parkindependent mitophagy. These data provide the first evidence for a neuroprotective role of TP53INP1/dDOR and highlight its involvement in the regulation of autophagy and mitophagy in neurons

Comparison of the data obtained by microarray and RT-qPCR for 6 genes of interest.

<p>(A) Genes specifically up-regulated by HFS, (B) opposite regulation of <i>Pkrcd</i> by HFS and DOPA and (C) common down-regulation of <i>Sirt5</i> by HFS and DOPA. Microarray experiments were performed on total striatal RNA samples from 6-OHDA, HFS, DOPA and DOPA/HFS groups. For qPCR validation of gene expression, total striatal RNA samples from 3 groups were analyzed: control, 6-OHDA and HFS. For both microarray and qPCR, results were calculated for each sample relative to the expression of the endogenous reference gene: HPRT, and fold change vs the 6-OHDA group was determined using the 2^−ΔΔCt method. Values are presented as means ± SEM. *p<0.05 vs 6-OHDA values.</p