Assistant Investigator, TIGEM
Drug and gene therapy for Parkinson’s disease.
Regardless of having genetic (10%) or idiopathic (90%) forms, Parkinson’s disease (PD) poses the greatest risk in the elderly. The disease is clinically characterized by prominent motor symptoms resulting from a progressive depletion in striatal dopamine. However, patients also experience troublesome non-motor deficits triggered by pathology in other neuronal systems. The current treatments only temporarily alleviate the symptoms, and therefore there is an unmet need for the discovery of a cure. The complexity of PD sets an incredible challenge for the research community in understanding the molecular mechanisms underlying this pathology, developing relevant, accurate and predictable animal models replicating cardinal features of the human condition, and identifying potential therapies.
Our lab is interested in studying these interconnected questions through a translational approach, extracting therapeutic strategies from molecular science. We believe that a better understanding of the pathology will ultimately lead to major discoveries. In particular, we investigate the function of the disease-causing protein, alpha-synuclein, in both physiological and pathological conditions. We showed that this protein dysregulates important signaling cascades that are essential for neuronal survival (Decressac et al., Science Transl. Med., 2012). For instance, neurotrophic factors such as GDNF (Glial cell line-derived neurotrophic factor) are interesting candidates for neurorestorative strategies. However the potential to introduce them to patients has been hampered by the poor translation of preclinical studies to the clinical setting. Using a novel rodent model of Parkinson’s disease, we uncovered a molecular mechanism by which alpha-synuclein disrupts the responsiveness of the dopamine neurons to the trophic factor and identified the transcription Nurr1 as a candidate target for therapeutic interventions.
We also develop innovative approaches to model the disease in vitro and in vivo (in different model organisms) and perform large screenings to identify targets that can mitigate its toxicity. We recently demonstrated that pharmacological or genetic stimulation of the transcription factor EB, which is a master regulator of autophagy and lysosomal biogenesis, promotes neuroprotection of nigral dopamine neurons (Decressac et al., PNAS, 2013). In line with this finding, a growing body of evidence suggests a link between lysosomal storage disorders (such as Gaucher disease) and PD.
Our objective is to identify potential therapeutic targets, validate them in relevant and complementary models of the disease, and finally, design clinically relevant strategies in order to bring them to the bedside.
Student: Irene Guadagnino, Sofie Bergstrand
Technician: Rossana Ippolito
Tamburrino A, Churchill MJ, Wan OW, Colino-Sanguino Y, Ippolito R, Bergstrand S, Wolf DA, Herz NJ, Sconce MD, Björklund A, Meshul CK, Decressac M(2015). Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson's disease. Acta Neuropathol Commun. 2015 Dec 14;3(1):84.
Decressac M, Volakakis N, Björklund A, Perlmann T (2013). NURR1 in Parkinson’s disease: from pathogenesis to therapeutic potential. Nat. Rev. Neurol. 9(11):629-36. doi:10.1038/nrneurol.2013.209.
Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björkund A (2013). TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. PNAS. 110(19):E1817-26. doi: 10.1073/pnas.1305623110.
Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Björklund A (2012). α-synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Science Translational Medicine. 4(163):163ra156. doi: 10.1126/scitranslmed.3004676.
Decressac M, Mattsson B, Lundblad M, Weikop P, Björklund A (2012). Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol. Dis. 45(3):939-53. doi: 10.1016/j.nbd.2011.12.013.