Investigating Chondroitin Sulphate Proteoglycans as a Therapeutic Target for Parkinson's disease

Student thesis: Doctoral ThesisDoctor of Philosophy


Parkinson's disease (PD) is characterised by the dopaminergic cell loss within the substantia nigra pars compacta of the basal ganglia. This pathology reduces the concentration of dopamine within the striatum and results in the cardinal motor dysfunctions we associate with the disease. Currently, therapeutic treatments such as L-DOPA merely act as symptomatic relief and do not slow disease progression; new PD therapeutics targeting neurorepair and protection are therefore in demand. In PD, remaining dopaminergic neurons possess limited capabilities for axonal regrowth and rewiring for reasons unknown. In this thesis, we suggest that the chondroitin sulphate proteoglycans (CSPGs) of the extracellular matrix may play a role in the inhibition of cellular recovery and in the aberrant plasticity associated with L-DOPA-induced dyskinesia. Previous studies have identified that the digestion of the CSPGs via the enzyme chondroitinase ABC (ChABC) permits axonal regeneration following brain injury. Here, for the first time, we investigate the efficacy of ChABC as a therapeutic strategy to aid cellular recovery in PD. The results presented in this thesis support the ChABC-mediated digestion of CSPGs within the nigrostriatal tract as a strategy of increasing cell survival within the 6-hydroxydopamine lesioned mouse. It was discovered that ChABC treatment enhanced dopaminergic cell survival in lesioned mice; no behavioural improvements were detected however. In a subsequent study, we aimed to further increase ChABC-mediated cell survival and induce behavioural improvements by increasing the striatal levels of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor by the administration of the MAO-B inhibitor selegiline. Although ChABC alone reproduced a similar degree of cell survival as before, the addition of selegiline did not improve cell survival or behavioural outcomes despite increasing neurotrophic factor levels during the first two weeks of experimentation. Moreover, selegiline decreased the efficacy of ChABC; perhaps a potential conflict between their pathways. Additionally, we investigated whether CSPGs and other cellular markers were upregulated in the striatum of L-DOPA-induced dyskinetic rats; a region identified to increase in volume within the dyskinetic state. Although CSPG expression did not increase, Iba1-positive microglial expression did. This suggests a role for microglia in L-DOPA-induced dyskinesia manifestation.
In conclusion, investigating the CSPGs as therapeutic targets is promising. However, identifying ways to enhance cell survival effects to induce detectable behavioural improvements is required. In order to do so, further investigations into the mechanism underlying the CSPG’s inhibitory nature would be a logical next step.
Date of Award2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSusan Duty (Supervisor) & Lawrence Moon (Supervisor)

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