INVESTIGATION OF NEUROPROTECTIVE TARGETS FOR PARKINSON’S DISEASE AND THEIR ROLE IN PATHOPHYSIOLOGY WITH A SECONDARY LOOK AT A MOLECULAR TARGET FOR SCHIZOPHRENIA

Abstract

Disorders of the central nervous system (CNS) continuously pose problems for current therapeutics. In part, this is due to the uncertainty of underlying pathophysiological changes that give rise to specific disorders. Parkinson’s disease (PD) specifically is a neurodegenerative CNS disorder with unknown origins of dopaminergic degeneration in the substantia nigra. Current therapies are reactive in nature and no existing neuroprotective therapies are available. Two hypotheses have been proposed to contribute to dopaminergic degeneration in PD: endoplasmic reticulum (ER) stress and oxidative stress. This thesis investigates molecular targets involved in each of these responses (mesencephalic astrocyte-derived neurotrophic factor (MANF) and cyclin-dependent 5 (CDK5)/p25 respectively) to support a multi-hit hypothesis in PD neural degeneration. Using behavioural and biochemical analysis, a reduction in MANF was found to participate in the ER stress hypothesis and CDK5/p25 hyperactivation is a viable neuroprotective target related to the oxidative stress hypothesis. Both pathways are evidenced in PD pathology and this thesis proposes specific targets for both pathways in the development of necessary neuroprotective therapies. Subsequently, included in this thesis is a chapter about the unmet pharmacological alleviation of negative and cognitive symptom domains in another CNS disorder of unknown pathophysiology: schizophrenia (SZ). These untreated symptoms are thought to be caused by irregularities in the signalling of multiple neurotransmitter systems. This chapter investigates the role of synapsin II, a protein involved in regulating signalling of multiple neurotransmitters, in manifesting negative and cognitive SZ symptoms and analyzes brain glucose metabolism. Reduced synapsin II levels were consistently implicated in the underlying physiology, and therefore synapsin II is proposed as a potential pharmacological target for these unmedicated symptomologies. Overall this thesis uses interrelated studies to propose novel molecular targets to address unmet therapeutic needs based on evidence of their involvement in the pathophysiology of PD and SZ.