How do autophagic-lysosomal dysfunction and protein aggregation impact on the risk of developing Parkinson’s disease?

How do autophagic-lysosomal dysfunction and protein aggregation impact on the risk of developing Parkinson’s disease?

Janelle Blades

I have recently completed a 6 week placement in the University of Reading Health and Life Sciences Laboratories as part of the Undergraduate Research Opportunities Programme (UROP). During the summer, between the second and third year of my Biomedical Sciences degree at Reading, I worked alongside Dr Susanna Cogo; shadowing her work, learning how to perform experiments independently and completing my own research. Whilst in the labs I also worked alongside PhD students and attended weekly meeting with scientists and PhD students in Reading and London to discuss their progress with research and collaborate ideas to enhance research further.

The focus of my project was ‘investigating the effects of lysosomal risk factors in LRRK2 Parkinson’s disease’. Parkinson’s disease (PD) is most common neurodegenerative movement disorder worldwide, and as an age-related disease, its prevalence is set to increase as the population ages (Mor et al, 2020). However, there remains no cure or effective treatment to revert the neurodegeneration seen in PD, as the underlying cause for this neurodegeneration is unknown. Despite continued research efforts, current treatments for PD are only effective at reducing the symptoms of PD, and often result in a number of adverse side effects or are impractical to administer to patients which makes them difficult for long term use. One genetic mutation which is known to cause PD is a mutation in the gene which encodes the protein leucine-rich repeat kinase 2 (LRRK2). LRRK2 protein is responsible for the transport and clearance of old material from cells, and so when mutated leads to an imbalance of material within the brain cells; this lead to the neurodegeneration seen in PD. Organelles known as lysosomes also play a key role in maintaining equilibrium within cells and so their function is often impaired by this LRRK2 mutation. The aim of this study was therefore to compare the function of lysosomes in Caenorhabditis elegans (nematode) models with and without the LRRK2 mutation. Since a number of other gene mutations linked to transport and clearance pathways within cells have been associated with an increased risk of developing PD, we also investigated whether these additional mutations had any further affects on C. elegans models with and without the LRRK2 mutation. Our results showed some differences in movement and protein expression in worms carrying the mutations, however, we will need to complete more replicas of this in order to identify any significant differences.

Overall, this experience benefited me hugely as I continue into my final year of my degree and work towards completing my dissertation and perusing a future career in lab work. I have developed numerous lab skills which will support me in my third year practicals and research for my dissertation, and also make me a competitive applicant for future job applications. Gaining these lab skills has been vital for me after the first year of my degree was completed online due to the pandemic and so I was unable to gain the hands-on practical experience from the very start. Having the opportunity to observe PhD students in the labs and attend their presentations also gave me an insight into an additional future pathway which I had not considered before. Completing my own research independently and then presenting this to a number of scientist and students who focus their work on C. elegans and PD enhanced my communication, data analysis and problem solving skills, and I look forward to developing these skills more as I complete my dissertation on PD.

Mor, D.E., Sohrabi, S., Kaletsky, R., Keyes, W., Tartici, A., Kalia, V., Miller, G.W. and Murphy,
C.T. (2020 Oct). Metformin rescues Parkinson’s disease phenotypes caused by hyperactive
mitochondria. Proceedings of the National Academy of Sciences of the United States of America.