José Ramón Naranjo
Group Leader
Research summary
We foresee the Ca2+-dependent transcriptional repressorDREAM as an active/central component of several nucleoprotein complexes that mediate specifically the various transcriptional cascades triggered by membrane depolarization in neurons or T cell receptor activation in lymphocytes.
Publications
Mellström B, Kastanauskaite A, Knafo S, Gonzalez P, Dopazo XM, Ruiz-Nuño A, Jefferys JG, Zhuo M, Bliss TV, Naranjo JR, DeFelipe J. Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice. Mol Brain. 2016 Feb 29;9:22
Naranjo JR, Zhang H, Villar D, González P, Dopazo XM, Morón-Oset J, Higueras E, Oliveros JC, Arrabal MD, Prieto A, Cercós P, González T, De la Cruz A, Casado-Vela J, Rábano A, Valenzuela C, Gutierrez-Rodriguez M, Li JY, Mellström B. Activating transcription factor 6 derepression mediates neuroprotection in Huntington's disease. J Clin Invest. 2016 Feb 1;126(2):627-38
Ruiz de Diego I, Mellström B, Vallejo M, Naranjo JR, Moratalla R. Activation of DREAM, a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice. Biol Psychiatry 2015; 77:95-105
Mellström B, Sahún I, Ruiz-Nuño A, Murtra P, Gomez-Villafuertes R, Savignac M, Oliveros JC, Gonzalez P, Kastanauskaite A, Knafo S, Zhuo M, Higuera-Matas A, Errington ML, Maldonado R, Defelipe J, Jefferys JG, Bliss TV, Dierssen M, Naranjo JR. DREAM controls the on/off switch of specific activity-dependent transcription pathways. Mol Cell Biol 2014; 34:877-887
Kreiner G, Bierhoff H, Armentano M, Rodriguez-Parkitna J, Sowodniok K, Naranjo JR, Bonfanti L, Liss B, Schütz G, Grummt I, Parlato R. A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell Death Differ 2013: 20:1455-1464
We study the nuclear components of activity- and Ca2+-dependent transcriptional responses in neurons and immune cells, to understand the molecular determinants of downstream events responsible for plastic changes in synaptic function. We also develop tools with which to intervene in physiological output processes including learning and memory, pain sensitisation and neurodegeneration.
Altered neuronal calcium homeostasis and early compensatory changes in transcription programs are common features of many neurodegenerative pathologies including Alzheimer’s (AD), Down syndrome (DS) and Huntington’s disease (HD). DREAM (DRE antagonist modulator), a Ca2+-dependent transcription repressor also known as calsenilin, has an important role in neurodegenerative diseases (NDD) through the control of Ca2+ homeostasis. Changes in DREAM levels are found in several mouse models of NDD, including AD, DS and HD. Genetic experiments show that this could be part of a neuroprotective mechanism.
We hypothesise the Ca2+-dependent transcriptional repressor DREAM as an active/central component of several nucleoprotein complexes that specifically mediate various transcriptional cascades triggered by membrane depolarization in neurons, which are essential in neuronal plasticity and synaptic dysfunction. Work in progress analyses the role of DREAM in regulating transcription in cell and animal models of NDD. Through these studies, we hope to better understand early changes in the transcriptome and epigenome and to explore new avenues for therapeutic intervention to boost early endogenous neuroprotective mechanisms.
