Evaluating the effect of senescence in alpha-synuclein accumulation-induced neuroinflammation and neurodegeneration in dopaminergic neurons

Doctoral study program: Neuroscience  

Specialization: Neuroscience

Form: doctoral full-time,

Department: Centre of Translational Medicine, International Clinical Research Centre, FNUSA Brno, CZ  

Supervisor: Amit Khairnar, Head Researcher, ICRC FNUSA, Ph.D.

Accumulation of alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Previous studies suggest that α-syn pathology may originate from the olfactory bulb (OB) or gut in response to an unknown pathogen and later progress to the different brain regions. Aging is viewed as the utmost threat to PD development. Therefore, studies depicting the role of age in α-syn accumulation and its progression in PD are essential. In our recent study, we gave intranasal rotenone microemulsion for 6 weeks in 12-month-old female BALB/c mice and found olfactory dysfunction after 4 and 6 weeks of rotenone administration.

Interestingly, motor impairment was observed only after 6 weeks. The animals were sacrificed after 6 weeks to perform western blotting and immunohistochemical studies to detect α-syn pathology, neuroinflammation, and neurodegeneration. We found α-syn accumulation in OB, striatum, substantia nigra (SN), and cortex. Importantly, we found significant glial cell activation and neurodegeneration in all the analyzed regions, which were absent in our previous published studies with 3 months old mice even after they were exposed to rotenone for 9 weeks indicating age is a crucial factor for α-syn induced neuroinflammation and neurodegeneration. Though we observed inflammaging as one factor involved in alpha synuclein induced neuroinflammation and neurodegeneration, we believe other pathways need to be explored which might be interesting in post-translational modification of alpha-synuclein ultimately causing degeneration which is not observed with young mice. Therefore, the current project will decipher the mechanism involved in aging, which is responsible for alpha-synuclein accumulation-induced dopaminergic neurodegeneration using in vitro and in vivo studies.

Funding for the research

Currently, the project is funded for around 3 years from the NPO project granted to FNUSA ICRC, and the student will get 9000 CZK extra in addition to a university fellowship for 3 years. The Ph.D. student is encouraged to apply for external funding like Brno's Ph.D. talent. Also, it is possible that once the pilot data is generated, more funding can be applied at the National and European Union levels.

 Requirements for the student, according to the Board for the Ph.D. studies Neuroscience at MU

The minimum publishing activity of the student within the Ph.D. study presents one review article in a peer-reviewed journal and one original article in a journal with IF over the median of the field, both related to the dissertation topic. Completion of an international study period of at least one month, which is mandatory for full-time doctoral students, or collaboration on an international project, including participation in regular project team meetings with results published or presented abroad or other forms of direct involvement in international cooperation. Participation in the teaching of Bachelor's and Master's programs or other educational activities in the workplace; you may also be entrusted with supervising or reviewing the final theses of students of Bachelor's or Master's programs, helping with examination organization, etc. Completion of compulsory courses: courses designed to broaden and enhance your knowledge in the field beyond the scope of Master's studies, courses designed to refine specialized understanding, and specialized seminars and lectures.

Supervisor

3 Ph.D. students already defended their Pre-PhD and submitted the thesis under the supervision of Amit Khairnar. The PI has published more than 27 international and peer-reviewed impacted journals with an H index of 13 and a total number of citations of more than 550. The PI was successful in receiving the Marie Curie fellowship. He was also the awardee of the prestigious Ramalingaswami fellowship for 5 years. He has completed many projects and has rich experience in developing progressive mouse PD models and understanding the pathology behind the development of alpha-synuclein pathology. In case of questions, it is possible to contact the supervisor: amit.khairnar@fnusa.cz, amitkhairnar520@gmail.com.