Day 3 :
- Novel Insights and Therapeutics for Parkinson’s Disease
Location: Raume / Room - 4
Chair
Kjell Fuxe
Karolinska Institutet, Sweden
Session Introduction
Jie Bai
Kunming University of Science and Technology, China
Title: Thioredoxin-1 suppresses MPP+/MPTP neurotoxicity through enhancing autophagy
Time : 10:00-10:30
Biography:
Jie Bai, now vice dean at Kunming University of Science and Technology, China. He established the ground-breaking neuroscience research programme on Parkinson’s disease (PD) with his novel human stem-cell-based cellular model of PD, aiming to find mechanism(s) of cell damage that leads cell towards death and development of the PD.
Abstract:
Autophagy is a lysosomal degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and misfolded protein. Autophagy is associated with the pathogenesis of Parkinson’s Disease (PD). Thioredoxin-1 (Trx-1) is a redox regulating protein and plays an important role in PD. However, the relationship between autophagy and Trx-1 in PD has not been reported. Cell and mouse models of PD were used to examine the relationship of autophagy and Trx-1. We showed that the expression of microtubule-associated protein light chain 3 (LC3-II), an auto-phagosome membrane marker was induced by 1-methyl-4-phenylpyridinium ion (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in PC12 cells and mice. Rapamycin autophagy inducer decreased toxicity by MPP+ in contrast to chloroquine autophagy inhibitor which increased toxicity by MPP+. These results suggest that autophagy plays a protecting role against MPP+ neurotoxicity. The over-expression of Trx-1 in PC12 cells and mice reversed LC3-II expression by MPP+/MPTP. Importantly, Forkhead box O3A (FOXO3A) expression was decreased by MPP+/MPTP in PC12 cells and Substantia Nigra pars compacta (SNpc) of mice. The decrease of FOXO3A was enhanced by down-regulation of Trx-1 and reversed by Trx-1 over-expression in mice. These results suggest that Trx-1 suppresses MPP+/MPTP neurotoxicity by enhancing FOXO3A/autophagy pathway. Our present study indicates FOXO3A may be a new potential target for treatment of PD.
Dasiel O Borroto-Escuela
Karolinska Institutet, Sweden
Title: On the role of A1-D1 heteroreceptor complexes in the direct pathway in models of Parkinson’s disease
Time : 10:30-11:00
Biography:
Dasiel O Borroto-Escuela has completed his PhD from Polytechnic University of Catalonia, Spain. Since 2009, he has been a Contracted Postdoctoral Researcher at the Department of Neuroscience, Karolinska Institutet. His primary focus is on understanding whether alterations in specific heteroreceptor complexes and if their receptor-receptor interactions are associated with and/or play a role in pathogenetic mechanisms contributing to brain disease development, inter alia Parkinson’s disease, schizophrenia, addiction and depression. He has received a significant number of awards, among which are the UPC Excellence Thesis Award, the FEBSYSF 2013, the ECNP 2014 Fellow Award. He has published over 70 papers in neuroscience in the last five years. His major achievements involve pioneering work on understanding the molecular integration of signals in the brain via receptor-receptor interaction in heteroreceptor complexes and its functional effects also, in the implementation of new innovative tools and screening technologies to identify GPCR oligomers.
Abstract:
Among a large number of behavioural studies on adenosine A1-Dopamine D1 receptor interactions, a few examples may be given. Thus, the A1 receptor agonist CPA counteracted the D1 receptor agonist (SKF 38393)-induced grooming behavior and counteracted dyskinetic behavior in rabbits. In line with these results, the A1 receptor antagonist CPT enhanced the motor activating effects of the D1 agonist SKF 38393 in reserpinized mice and in rat models of Parkinson’s disease (unilateral 6-OH-dopamine lesions of the nigrostriatal dopamine pathway). This behavioural result at the network level indicates the existence of antagonistic A1-D1 receptor interactions. The molecular basis of the antagonistic A1-D1 receptor interaction likely involves the existence of A1-D1 heteroreceptor complexes in the direct pathway. The A1-D1 heteroreceptor complexes may reflect a direct physical interaction without the involvement of an adapter protein, since specific BRET and FRET signals can be detected between fluorescent-tagged A1 and D1 receptors upon transient co-transfection in cell lines. Furthermore, in situ Proximity Ligation Assay clearly demonstrated that A1 and D1 receptors exist as heteroreceptor complexes in rat brain. Antagonistic A1-D1 interactions also exist at the level of the second messengers. These results suggest a role of A1 receptor agonists and antagonists in the treatment of Parkinson’s disease with dysfunction of D1 receptor signaling via their actions on the A1-D1 heteroreceptor complexes located in the direct pathway. A1 agonists may, for example, reduce levodopa induced dyskinesias. It will be of substantial interest to know how the A1-D1 receptor interaction may regulate trophic mechanisms such as neurotrophic factors and neuronal differentiation.
Kjell Fuxe
Karolinska Institutet, Sweden
Title: The impact of DA heteroreceptor complexes and their receptor-receptor interactions in Parkinson’s disease and its treatment
Time : 11:30-12:00
Biography:
Kjell Fuxe is a Professor of Histology at Karolinska Institutet since 1979. He was the Member of Nobel Assembly from 1986-2005. He achieved his Honorary Doctorates at the Universities of Barcelona, Ferrara, Malaga, at Universite Claude Bernard, Lyon, at Marquis Guiseppe Scicluna International University Foundation and at the Albert Einstein International Academy Foundation. He has received a significant number of awards and published over 1500 papers in neuroscience. 1209 of them are found in Pubmed. His major achievements involve pioneering work on central monoamine neurons, the existence of volume transmission, receptor-receptor interactions in heteroreceptor complexes and in neuro-endocrinology and neuro-psychopharmacology.
Abstract:
Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. Changes in the function of the DA heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson’s Disease (PD) with levodopa and DA receptor agonists. In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD will be covered; and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes in PD will be covered. D1R and D2R heteroreceptor complexes in the brain open up a new understanding of the wearing-off of the anti-Parkinson actions of levodopa and DAR agonists and the production of levodopa induced dyskinesias. Today, it seems as if the major advantage of DA receptor agonists is that they can postpone, in early PD, the use of levodopa which gives a higher incidence of dyskinesias in PD patients vs. ropinirole and pramipexol. The motor complications can involve a reorganization of the D1R and D2R heteroreceptor complexes and a dis-balance of the D1R and D2R homomers versus non- DA receptor homomers in the direct and indirect pathways. Through understanding these mechanisms, new strategies for the treatment of motor function deficits in PD can be offered with reduced motor complications. However, the motor deficits due to degeneration of non-dopaminergic neurons will remain.The relevance of interactions of the receptor protomers in the signaling cascades and the transcriptional regulation will also be discussed including downstream target proteins.
Jose L Lanciego
Center for Applied Medical Research, Spain
Title: New gene therapy approaches for Parkinson’s disease
Time : 12:00-12:30
Biography:
Jose L Lanciego has completed his PhD from the University of Salamanca Medical School and Postdoctoral studies from Amsterdam Vrije Universiteit. He is the Director of the Basal Ganglia Neuroanatomy Lab at the Center for Applied Medical Research (CIMA). He has published more than 80 papers in international scientific journals and he is serving as an Editorial Board Member of Brain Structure and Function as well as Associate Editor of Frontiers in Neuroanatomy. His main research interests include a number of topics dealing with the pathophysiology of Parkinson’s and Alzheimer’s diseases.
Abstract:
The field of Gene Therapy in the CNS has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify brain circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by induced changes in brain circuits. Here, we will illustrate the rationale behind several experiments that are currently under implementation in the Non- Human Primate (NHP) model of Parkinson’s Disease (PD). Among others, we will focus on the following approaches: (1) In vivo reconstruction of the nigro-striatal pathway, (2) Selective elimination of hyperactive basal ganglia circuits in dyskinetic macaques and (3) Strategies for in vivo reprogramming of striatal neurons. Besides considering the translational potential of these approaches, we hope that these experiments, complementary to each other, will allow us to generate new data supporting a better understanding of the pathophysiology of PD.