Investigating the stratification of Parkinson disease patients by markers of systemic mitochondrial dysfunction

Parkinson disease (PD) is a common neurodegenerative movement disorder, for which there are currently no treatments to halt or slow its relentless progression. It is likely that the failures in identifying disease modifying therapies, at least in part, relate to aetiopathological heterogeneity within PD. Given this, there is a growing body of work aiming at stratification of PD cohorts by disease mechanisms, such as mitochondrial dysfunction, with a view to offering precision treatments. To that end, the aim of this thesis was to explore the use of systemic bioenergetic dysfunction as a tool for stratifying PD patients. I first optimised a battery of complimentary assays of bioenergetic function, including measures of respiration, mitochondrial membrane potential (Δψm) and total ATP levels, for the assessment of peripheral blood mononuclear cells (PBMCs). Using the optimised protocols I then explored PBMC bioenergetic function in healthy control subjects to explore the effect of age, gender, cigarette smoking status, medication use and medical comorbidities on bioenergetic function. I demonstrated that both age and smoking status have significant impacts on PBMC bioenergetic function. I next went on to explore bioenergetic function in cohorts of monogenic PD patients, specifically those with PRKN, GBA1 and LRRK2 related PD. PBMCs from PRKN-PD patients were found to have significantly reduced ATP-linked respiration, maximal respiration and spare respiratory capacity, as well as reduced mitochondrial membrane potential in both lymphocyte and monocyte subpopulations. In addition PRKN-PD samples were associated with significantly increased proton leak respiration. GBA1-PD PBMCs were found to have reduced monocyte mitochondrial membrane potential, but all other bioenergetic parameters were similar to controls. LRRK2-PD and PRKN-het PD patient samples had similar bioenergetic parameters to controls. Using the parameters that best distinguished monogenic PD from controls, I created a composite score representing overall bioenergetic function. This score was then used to stratify a large cohort of idiopathic PD patients, to define subgroups with and without significant bioenergetic impairment. I was able to show that those patients with significant bioenergetic impairment had a significantly earlier age of onset, however all other clinical measures were similar between those with and without significant bioenergetic impairment suggesting that clinical markers alone are not a good surrogate for underlying bioenergetic function. Interestingly, those PD patients with significant bioenergetic impairment had higher mitochondrial polygenic risk scores than those without significant bioenergetic function.