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Exploring pre-degenerative alterations in human models of Parkinson’s disease using induced pluripotent stem cell (iPSCs)-derived dopaminergic neurons
Universita degli Studi di Brescia
Department of Molecular and Translational Medicine- Pharmacology
Type of Research Project
- Basic science
What is the background of the project?
We recently found that in mouse and induced pluripotent stem cells (iPSCs)-derived human dopaminergic (DA) neurons, dopamine D3 receptor (D3R) and the beta2-containing nAChR interact to form a molecular entity (D3R-nAchR heteromer) that is crucial for DA neurons function. We found, in fact, that activating the D3R-nAchR heteromers by DA agonists or by nicotine, significantly enhanced soma size and dendritic arborization and protected neurons against toxic stimuli. Therefore, it is likely that defects in D3R-nAchR heteromer activity may represent a molecular alteration that might affect DA neurons homeostasis and eventually contribute to make these neurons more vulnerable, as occurs in Parkinson’s disease (PD). PD is a severe neurological disorder characterized by the progressive degeneration of nigrostriatal DA neurons; while the majority of PD cases are sporadic, a proportion of PD are linked to genetic mutations, including mutations in the LRRK2, alpha synuclein and PINK1 genes. Despite the severity of the disease, the mechanisms underlying DA neurons degeneration are still largely unknown.
What is the aim of the project?
The aim of this project is to investigate wether in DA neurons, genetic mutations associated with PD development impact on D3R-nAChR heteromer physiological localization and function, IFMSA International Secretariat, c/o IMCC, Nørre Allé 14, 2200 København N., Denmark thus representing a pre-degenerative molecular event underling DA neuron vulnerability.
What techniques and methods are used?
The study will be developed by using iPSCs derived from PD patients carrying mutations in PD-associated genes such as LRRK2, alpha syn and PINK1, as well as from gene-corrected iPSCs lines of the same patients and from healthy control. iPSCs will be differentiated into mixed neuronal cultures containing DA neurons along with glutamatergic and GABAaergic neurons iPSCs-derived neurons will be analysed for D3R/nAchR complex localization and function by using a combination of biochemical and immunological approaches, including immunocytochemistry, morphological staining, proximity ligation assay, western blot analyses.
What is the role of the student?
- If the project includes “lab work”
- the student will take active part in the practical aspect of the project
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will have to understand the aim of the project reading scientific articles from principal scientific databases. After, the student will have to take part in the laboratory experiments, having the the opportunity to learn about the basic biochemical techniques, commonly used for studying receptor and heterodimer expression, localization and function, such as cell cultures techniques, Western Blot analyses and immunocytochemistry. Moreover, the student will work together with the tutor in the design of experiments and analysis of results.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The student will have to read scientific articles provided by the tutor. Moreover, under supervision, the student will have to search in literature the last key articles on the topic of the project. The student will have to read and discuss them with the Tutor.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
The student should have a good background in neurobiology and pharmacological sciences
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system
- Bono F; Savoia P; Guglielmi A; Gennarelli M; Piovani G; Sigala S; Leo D; Espinoza S; Gainetdinov RR; Devoto P; Spano P; Missale C; Fiorentini C (2018) Role of Dopamine D2/D3 Receptors in Development; Plasticity; and Neuroprotection in Human iPSC-Derived Midbrain Dopaminergic Neurons. Mol Neurobiol 55(2):1054-1067. (IF 2018: 4;5)
- Bontempi L; Savoia P; Bono F; Fiorentini C; Missale C (2017) Dopamine D3 and acetylcholine nicotinic receptor heteromerization in midbrain dopamine neurons: Relevance for neuroplasticity. Eur Neuropsychopharmacol. 27(4):313-324. (IF 2018: 4;4)
- Bono F; Fiorentini C (2017) Exploring pre-degenerative alterations in humans using induced pluripotent stem cell-derived dopaminergic neurons. Neural Regen Res. 12(7):1068-1070. (IF 2018: 2;4)
- Bono F; Mutti V; Savoia P; Barbon A; Bellucci A; Missale C*; Fiorentini C* (2019) Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3- acetylcholine nicotinic receptor heteromer. Neurobiol Dis. 129:1-12. doi: 10.1016/j.nbd.2019.04.017. (*co-senior authors). (IF 2018: 5;1)
- Matera C; Bono F; Pelucchi S; Collo G; Bontempi L; Gotti C; Zoli M; De Amici M; Missale C; Fiorentini C*; Dallanoce C* (2019) The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons. Biochem Pharmacol. 163:154-168. (*co-senior authors). (IF 2018: 4;8)
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