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Investigating the role of alpha-synuclein strains in neurodegeneration in preclinical models for multiple system atrophy
Belgium (BeMSA) - KU Leuven, Leuven
Department of Neurosciences - Laboratory for Neurobiology and Gene Therapy
Prof. Veerle Baekeland
Type of Research Project
- Basic science
What is the background of the project?
Misfolded protein aggregates appear to be a common feature of several ageing-related neurodegenerative diseases. The major neuropathological hallmark in Multiple System Atrophy (MSA) and related diseases such as Parkinson's disease (PD) are alpha-synuclein (αSYN) protein deposits1. We propose that different aggregated protein conformations or 'strains' are at the origin of the heterogeneous nature of the synucleinopathies. As support of this hypothesis we have previously shown that inoculating different synthetic ɑSYN strains results in distinct histopathological features in vivo that resemble PD and MSA (Peelaerts et al., 2015, Nature). In this project we will translate our previous findings to human disease by investigating the properties of αSYN-rich fractions from the brain of MSA patients in novel rodent models. We will use viral vector technology that allows specific expression of ɑSYN in oligodendroglial or neuronal cells. By combining and comparing the inoculation of ɑSYN derived from patients in the presence of varying levels of ɑSYN expression in different cells we will assess their ability to induce MSA or PD pathology in the rat brain.
What is the aim of the project?
Reproduce human MSA pathology via viral vector-mediated overexpression of human ɑSYN after seeding with patient-derived human ɑSYN strains in vivo.
What techniques and methods are used?
Viral vector technology to express α-SYN specifically in oligodendrocytes. Stereotactic neurosurgery in rat brain Behavioural studies (cylinder test) to assess motor function Assessment of neuropathology by western blot, immunohistochemical stainings and microscopic evaluation (fluorescence and lightfield). Image analysis and stereological quantifications of microscopic evaluations. During all the procedures student has to collect data in order to make data analysis via Excel.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- 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 is expected to get familiarized with the project background and main techniques by reading relevant scientific literature. The student will follow and assist ongoing experiments. The student is expected to learn basic handling in a number of techniques, such as western blotting, sectioning of rat brain, immunohistochemical stainings, light and fluorescent microscopy. By the end of the internship the student should be able to understand the project background and experimental set-up, to analyse and interpret the obtained results in the context of the project. During all the procedures student has to collect data in order to make data analysis via Excel. Excel knowledge are mandatory.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Background literature will be provided to the student to understand the project. If the occasion is there, the student can also attend relevant seminars
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic knowledge of molecular and cell biology and principles of neuroscience. Expertise with laboratory techniques and animal experiments is a plus
Are there any legal limitations in the student’s involvement
Animal work can only be performed by a Federation of European Laboratory Animal Science Associations (FELASA) certified student
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Students in biomedical fields
- Peelaerts; W. et al.; Nature 522; 340-4 (2015).
- Bousset; L. et al.; Nat Commun 4; 2575 (2013).
- Fellner; L.; Wenning; G.K. & Stefanova; N.; Curr Top Behav Neurosci 22; 369-93 (2015).
- Prusiner; S.B. et al.; Proc Natl Acad Sci USA 112; E5308-17 (2015).
- Peng et al; Nature 557; 7706 (2018)
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