Mutations in the PINK1 gene were recently linked to autosomal recessive parkinsonism. However, to date, very little is known about the role of PINK1 in the brain. Our group has ample expertise with stereotactic delivery of lentiviral vectors (LVs) in mouse and rat brain for the overexpression or RNAi-mediated knock-down of PD-related genes. This cutting-edge technology provides us with an excellent and fast tool for an in vivo functional study of PINK1 in rodent brain. We therefore propose to develop lentiviral vectors for targeted overexpression and inhibition of PINK1 in different regions of mouse and rat brain. We will investigate whether manipulation of PINK1 expression levels in adult brain can induce or modulate Parkinson's disease-related neuropathology.
Final Outcome
Dr. Baekelandt tested several lentiviral vector approaches to overexpress normal or mutated PINK1 or to deliver RNAi constructs to knock down PINK1 in the substantia nigra of adult rodents. Dr. Baekelandt generated interesting research tools for studying PINK1 function. However, additional work is needed to optimize the use of these tools to determine the normal and pathological role of PINK1 in brain as technical problems limited her ability to get meaningful results, although she did find apparent loss of dopamine neurons after PINK1 knockdown.
Follow-on funding for additional studies was provided by several European funding agencies.