Profound cholinergic neuronal loss occurs in the pedunculopontine nucleus (PPN) of Parkinson's disease patients compared to age-matched control cases. This loss is believed to underlie the gait disturbances seen in PD patients. Previously, our group (Pienaar et al. 2013) reported loss of neurons producing γ-aminobutyric acid (GABA) and glycine, two major inhibitory neurotransmitters. Interestingly, when expression of proteins that play a key role in the mitochondrial electron transport chain (for producing energy (ATP) to meet energy demands of the cells) were evaluated, significant up-regulation of such proteins were seen in GABAergic and glycinergic neurons; however, cholinergic neurons showed down-regulation of the same proteins. These findings lead to intriguing speculations as to the molecular mechanisms that might underlie deep brain stimulation (DBS) of the PPN, which improve gait disturbances in PD patients. A Ph.D. studentship (42 months) is available from February 2018 under the supervision of Dr. Ilse Pienaar, School of Life Sciences, University of Sussex, to investigate the molecular basis of our previous findings. In particular, the project will explore the degree of mitochondrial dysfunction that PPN neurons undergo, which may be due to oxidative stress, mitochondrial DNA mutations during replication, altered mitochondrial structure and the interaction of pathogenic proteins such, as the aggregate-prone protein α-synuclein with mitochondria, with all these factors that could play a defining role in the neurodegeneration affecting PD patients.

We have also developed novel drug molecules, which will be tested for the ability to target mitochondrial dysfunction and related oxidative stress, and thereby hold significant potential in the treatment of PD.

This PhD project will allow a student to gain expertise in mitochondrial genetics, -genomics, medicinal chemistry, biochemistry (particularly mitochondrial bioenergetics), cell culturing technologies, and computational modelling, applied to understanding the progressive neurodegeneration seen in PD. The work will be conducted in collaboration with laboratories in Germany, hence giving the successful applicant the opportunity to perform some of the experimental work there.