Open Access Repository

Investigating differential cellular and regional vulnerability to alpha-synuclein pathogenesis in the cortex


Downloads per month over past year

Salter, AJ ORCID: 0000-0003-2873-966X 2021 , 'Investigating differential cellular and regional vulnerability to alpha-synuclein pathogenesis in the cortex', Research Master thesis, University of Tasmania.

PDF (Whole thesis)
Salter_whole_th...pdf | Download (24MB)

| Preview


Aggregated alpha-synuclein (a-syn) is a major pathological feature in the brain of people with Parkinson’s Disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA). Collectively these diseases are known as ‘synucleinopathies’. Experimental evidence implicates cellular stress, particularly calcium dyshomeostasis, as a potential trigger of pathogenic a-syn aggregation. Cell-autonomous features, including calcium-binding protein (CBP) expression, appear to be key determinants of differential vulnerability in synucleinopathies, as neurons expressing CBPs are spared from a-syn pathogenesis and degeneration in PD and DLB. The substantia nigra (SN) is a characteristic site of a-syn pathology and neurodegeneration in PD, however the cortex is the main site affected in DLB, and is also affected in PD. Importantly, not all brain regions are affected in synucleinopathies, suggesting that vulnerability to a-syn pathogenesis may be region specific. Further characterising the physiological features that influence the differential vulnerability of cortical neurons may expand the current understanding of the mechanisms underlying both a-syn pathogenesis and selective vulnerability in synucleinopathies.
To investigate the role of calcium dyshomeostasis in neuronal vulnerability to a-syn pathogenesis, intracellular calcium levels within primary cortical mouse neurons were manipulated to determine the effect on endogenous a-syn. Calcium dysregulation, induced by 50mM KCl, significantly increased a-syn level in cortical neurons after 24 hours, and did not adversely affect cortical neuronal viability. A significant reduction in neuron density 24-hours post-treatment indicated that a specific population of neurons not expressing a-syn may have undergone apoptosis in response to calcium dysregulation. In specific populations of excitatory pyramidal neurons expressing YFP, and inhibitory neurons expressing Calretinin (CR), a-syn level was unchanged, and neuron health was unaffected, suggesting that these cortical neuron ypes may be more resistant to endogenous a-syn changes and apoptosis following calcium dysregulation.
To further investigate the factors that may influence regional differences in vulnerability to asyn pathogenesis, the density of neurons expressing the CBPs Calbindin (CB) and CR, and the L-type voltage-gated Cav1.2 calcium channel, were quantified and compared in regions of the cortex both spared and affected by a-syn pathology in human post-mortem PD tissue. Pathological a-syn was identified in the frontal and parietal cortices, but was rarely observed in the occipital cortex. However, no cell loss was observed in any cortical region in PD compared to age-matched controls. The density of neurons expressing CB, CR or the Cav1.2 channel did not differ in the frontal or parietal cortices in comparison to the relatively spared occipital cortex in PD, nor between PD cases and age-matched controls.
The findings from this thesis suggest that expression of endogenous a-syn, and the ability to upregulate a-syn, may be neuroprotective in response to calcium dysregulation in primary cortical neurons. No association was identified between the neuronal expression of CBPs or Cav1.2, and the density of a-syn pathology in regions of the human cortex in PD. In conclusion, this thesis provides evidence that calcium dysregulation can induce changes in endogenous a-syn in primary cortical neurons. However, it remains unclear whether neuronal, and thus regional vulnerability, of the cortex in PD is primarily determined by calcium-dependent mechanisms.

Item Type: Thesis - Research Master
Authors/Creators:Salter, AJ
Keywords: Parkinsons disease, alpha-synuclein, neuronal vulnerability, calcium dyshomeostasis, central nervous system
DOI / ID Number: 10.25959/100.00037904
Copyright Information:

Copyright 2021 the author

Item Statistics: View statistics for this item

Actions (login required)

Item Control Page Item Control Page