COMPUTATIONAL PREDICTION OF BIOCHEMICAL COMPENSATORY MECHANISMS IN SUBJECTS AT RISK OF DEVELOPING PARKINSON’S DISEASE.

Doctoral thesis (2018)

Parkinson’s disease (PD) is characterised by the degeneration of substantia nigra pars compacta dopaminergic neurons. These neurons have a highly complex axonal arborisation and a high energy demand, so ... [more ▼]

Parkinson’s disease (PD) is characterised by the degeneration of substantia nigra pars compacta dopaminergic neurons. These neurons have a highly complex axonal arborisation and a high energy demand, so any reduction in ATP synthesis could lead to an imbalance between demand and supply, thereby impeding normal neuronal bioenergetic requirements. The notion of energy metabolism inevitably implicates mitochondria, the cells’ main powerhouses, linking glycolysis to oxidative phosphorylation. In the brain, there are two types of mitochondria, with synaptic mitochondria localised to neuronal synapses and somal mitochondria localised to glial or neuronal somata. It has long been known that synaptic and somal mitochondria differ in their localisation, substrate utilisation, and enzymatic activities. For example, after biogenesis in and transport from the soma, synaptic mitochondria become highly dependent upon oxidative phosphorylation and exhibit increased vulnerability to dysfunction in PD, as opposed to somal mitochondria. Since the description of the disease by the London apothecary James Parkinson in 1817 and after more than two hundred years of descriptive research, we envisaged that quantitative computational modelling of PD will allow a cumulative, formal synthesis of the results of this research to occur. Clearly not all at-risk subjects actually develop PD, the open question is why? Are there biochemical compensatory mechanisms that protect some at-risk individuals from developing PD? We addressed this question using constraint-based computational modelling of dopaminergic neuronal metabolism, because we hypothesised that the existence of metabolic compensatory mechanisms can be predicted using comprehensive models of healthy, albeit at risk, and diseased dopaminergic neurons. A systems biochemistry approach was applied to identify the metabolic pathways used by neural models for energy generation. The mitochondrial component of an existing manual reconstruction of human metabolism (Recon 3D) was extended with manual curation of the biochemical literature and specialised using omics data from PD patients and controls, to generate reconstructions of synaptic, somal, and astrocytic metabolism. Following the imposition of experimentally-derived constraints, these reconstructions were converted into stoichiometrically- and flux-consistent constraint-based computational models. These models predict that PD is accompanied by a failure of the nigrostriatal glycolytic pathway and that in silico perturbations to non-trivial reaction rates may be able to rescue this bioenergetic phenotype. This is consistent with independent experimental reports where the enhancement of glycolysis was shown to provide neuroprotection in PD. This is the first application of biochemical network modelling used for the prediction of novel putative metabolic targets: a step closer towards the treatment of idiopathic PD. [less ▲]