We study signal transduction mechanisms involved in neurodegenerative and neuropsychiatric disorders, such as Parkinson’s disease, schizophrenia and drug addiction. We have been particularly interested in the study of dopamine transmission, which is profoundly affected in all these conditions.
Our final goal is to identify molecular changes, which may represent novel targets for therapeutic interventions. Methodology is based on a combination of molecular biological, biochemical and behavioral techniques. Disease modelling coupled to cell-targeted expression of fluorescent proteins is used to investigate abnormal signaling and gene expression at the level of discrete groups of neurons. In parallel, specific signaling components are studied at the biochemical and behavioral level using pharmacological tools, or by manipulating their expression both systemically and in a cell-specific manner. Using these strategies we have characterized key molecular events involved in the effects of various classes of psychoactive drugs. We have also identified abnormalities in signal transduction affecting distinct neuronal populations and underlying the severe motor complications, or dyskinesia, caused by prolonged administration of L-DOPA to parkinsonian patients. More recently, we have started to investigate the mechanisms at the basis of non-motor symptoms of PD, which include cognitive impairment and neuropsychiatric conditions, such as depression and anxiety.
We are also studying the effects of typical and atypical antipsychotic drugs on signal transduction processes in various brain regions.
Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32.
Valjent E, Bertran-Gonzalez J, Bowling H, Lopez S, Santini E, Matamales M, et al
Neuropsychopharmacology 2011 Nov;36(12):2561-70
Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism.
Santini E, Feyder M, Gangarossa G, Bateup H, Greengard P, Fisone G
J. Biol. Chem. 2012 Aug;287(33):27806-12
Cognitive impairment and dentate gyrus synaptic dysfunction in experimental parkinsonism.
Bonito-Oliva A, Pignatelli M, Spigolon G, Yoshitake T, Seiler S, Longo F, et al
Biol. Psychiatry 2014 May;75(9):701-10
Dopamine signaling leads to loss of Polycomb repression and aberrant gene activation in experimental parkinsonism.
Södersten E, Feyder M, Lerdrup M, Gomes AL, Kryh H, Spigolon G, et al
PLoS Genet. 2014 Sep;10(9):e1004574
A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FosB Expression.
Feyder M, Södersten E, Santini E, Vialou V, LaPlant Q, Watts EL, et al
Biol. Psychiatry 2016 Mar;79(5):362-371