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Insights into the molecular mechanism of cell death in Parkinson’s Disease

Yao, Z.; (2011) Insights into the molecular mechanism of cell death in Parkinson’s Disease. Doctoral thesis , UCL (University College London).

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Parkinson’s disease (PD), affecting about 1% of the population over 60 years old, is the second most common neurodegenerative disease. Although the majority of PD cases are sporadic, mutations in a number of genes are known to cause or increase the risk of developing PD. Studying the function of these genes can shed light on our understanding of the molecular mechanisms contributing to both familial and sporadic forms of PD. This thesis is focused on two of these genes: PINK1 and LRRK2. Mutations in the PINK1 gene are the second most common cause of autosomal recessive forms of PD. PINK1 is a serine/threonine kinase with a mitochondrial targeting sequence. Studies have suggested a neuroprotective role for PINK1 and loss of PINK1 function can lead to mitochondrial dysfunction, increased oxidative stress, altered mitochondrial fission/fusion and autophagy. In this study, I have investigated the effects of PINK1 deficiency on mitochondrial and cellular function as well as brain and skeletal muscle pathology using a PINK1 knockout (KO) mouse model. Although aged PINK1 KO mice don’t develop obvious pathological changes (e.g. neurodegeneration or abnormal protein aggregation), PINK1 KO leads to impaired mitochondrial respiration in both midbrain neurons and skeletal myocytes. The difference in cellular energy metabolism between these two cell types determines their different responses to PINK1 deficiency in terms of mitochondrial membrane potential and calcium regulation, which may explain the selective vulnerability of neurons to PINK1 associated PD. In addition to this work, I have also studied the expression and distribution of putative LRRK2 substrates, ERM (ezrin, radixin and moesin) proteins, in PD brains compared to healthy controls. Mutations in the LRRK2 gene are the most common cause of autosomal dominant forms of PD. LRRK2 is a large protein kinase with multiple functional domains. ERM proteins have been demonstrated as putative LRRK2 substrates by in vitro assays. In this study, I examined the expression levels and distribution of moesin and phospho-ERM proteins in post-mortem PD brains and found that the level of phospho-ERM was increased in striatum from sporadic PD brains compared to controls. Furthermore, phospho-ERM proteins were localized to Lewy bodies, one of the main PD pathological hallmarks, in both IPD brains and brains of PD patients carrying the G2019S LRRK2 mutation. These results suggest that ERM proteins might play a role in the pathogenesis of PD.

Type: Thesis (Doctoral)
Title: Insights into the molecular mechanism of cell death in Parkinson’s Disease
Language: English
Additional information: Permission for digitisation not received
UCL classification: UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
URI: http://discovery.ucl.ac.uk/id/eprint/1310579
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