Alpha-synuclein post-translational modifications and abnormal network oscillations in Lewy body dementias

Abstract

Lewy body dementias (LBDs) are age related neurodegenerative diseases characterized by the presence of abnormal alpha-synuclein (αSyn) inclusions termed Lewy Bodies (LBs) and Lewy Neurites (LNs) and represent the second most common form of neurodegenerative dementia after Alzheimer’s disease. LBDs are progressive pathologic conditions with variable clinical signs and symptoms including dementia and abnormal neuronal network oscillations, with no currently available treatment. The interaction between αSyn post-translational modifications (PTMs) and neuronal dysfunction is a core concept in LBDs. Accumulating evidence shows that, αSyn PTMs, such as, phosphorylation, ubiquitination and nitration, are events that occur in the context of synucleinopathies. I hypothesised that these PTMs lead to the formation of toxic/aggregated forms of αSyn that causes neuronal dysfunctions/death and impair neuronal network oscillations. The aim of this thesis was to Identify the PTMs of αSyn, analyse their distribution in LBDs, correlate them with the distribution of parvalbumin expressing interneurons in in post-mortem brain tissues of LBD patients, and analyse its links with mitochondrial dysfunction and neuronal network impairments. Using, electrophysiological and immunohistochemical protocols in selected cases that fulfilled the neuropathological criteria for LBDs and control cases, sourced from Newcastle Brain Tissue Resource (NBTR), and Transgenic A30P and control C57BL6 mice from comparative biology centre (CBC), I found that aged A30P mice had greater sensitivity to the mitochondrial inhibition by reducing the area power of the gamma frequency oscillations. In addition, parvalbumin expressing cells are significantly altered in humans, specifically in areas associated with the development of prodromal stages of LBDs, these same areas correlated with regions that presented higher Burden of αSyn phosphorylation. In conclusion, this thesis demonstrates that, reduction in density of parvalbumin cells depicts the impairments in gamma frequency oscillations and correlates with an increase in αSyn PTMs in some regions of LBD patients.