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Title: Investigating the contribution of synaptic and vascular pathology to neurodegeneration in mitochondrial disease
Author: Chrysostomou, Alexia
ISNI:       0000 0004 5990 4274
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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Mutations in mitochondrial DNA (mtDNA) lead to a genetically and phenotypically heterogeneous group of human diseases, mitochondrial disorders. Though patients with mtDNA disease present with multisystemic abnormalities, the central nervous system is usually severely affected. Of the neurological deficits, cerebellar ataxia is the most frequently presenting symptom of patients recruited to the UK MRC Mitochondrial Disease Patient cohort, with a prevalence of 70%. Furthermore, stroke-like episodes are prominent, but not restricted, to patients with the Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) syndrome, due to the m.3243A > G point mutation. Both neurological symptoms are associated with pronounced neurodegeneration. The aim of this thesis was to gain further insights into the mechanisms responsible for neuronal loss in patients who manifest with cerebellar ataxia and stroke-like episodes. A reliable, reproducible and quantitative quadruple immunofluorescent technique has been developed that allowed the quantification of respiratory chain protein expression in specific neuronal domains and cellular populations. Furthermore, three-dimensional reconstruction helped examine the structural characteristics of sub-cellular compartments. Close investigation of the intracerebellar microcircuitry provided evidence for respiratory chain protein expression defects in Purkinje cell bodies, dendrites and presynaptic terminals. Altered Purkinje cell innervation of respiratory chain deficient dentate nuclei neurons likely leads to neuronal disinhibition and is accompanied by partially disturbed glutamatergic connectivity to the region. Additionally, respiratory chain deficiencies were detected in the vasculature of vulnerable to stroke-like episodes brain regions (cerebellum, occipital and temporal lobe) in patients harbouring the m.3243A > G point mutation. Preliminary data suggest that stroke-like episode manifestation and cortical lesion development is due to an additive effect between neuronal/interneuronal and vascular pathology. These observations set the basis for studying the impact of mtDNA defects in synaptic, neuronal and vascular health in-vitro and have important implications for identifying good candidates for drug targeting in mitochondrial disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available