Autophagy-lysosomal pathway dysfunction in Parkinson’s disease

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Copyright: Murphy, Karen
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Abstract
Lysosomes degrade intracellular proteins through autophagy-lysosomal pathways (ALP), including macroautophagy and chaperone-mediated autophagy (CMA). Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterised pathologically by abnormal α-synuclein protein inclusions in neurons, indicating impaired ALP degradative capacity in PD. Heterozygous GBA1 mutations, encoding lysosomal glucocerebrosidase (GCase), are the greatest genetic risk factor for PD, and reduced GCase and α-synuclein accumulation are related in PD models. This thesis characterised relationships between increased α-synuclein, reduced GCase and ALP dysfunction in PD brain tissue, and hypothesised that ALP dysfunction precedes abnormal α-synuclein accumulation in PD-affected regions, with increasing lysosomal dysfunction in later disease stages and when heterozygous GBA1 mutations are present. Brain tissue from regions with and without PD-related α-synuclein accumulation was assessed in early (Braak stage IV) and later (Braak stages V/VI) stage sporadic PD and GBA1-mutant PD (Braak stages V/VI). The selective early increase in membrane-associated α-synuclein prior to substantial inclusion formation and neuron loss was confirmed in early stage PD, with greater α-synuclein levels and neuron loss evident in later disease stages. Reduced levels of lysosomal GCase were associated with increased α-synuclein in sporadic PD, while more severe GCase enzyme activity deficits were identified in GBA1-mutant PD that did not relate to α-synuclein. Early dysregulation of CMA was associated with increased α-synuclein and reduced GCase in sporadic PD, while additional macroautophagy deficits were related to the greater GCase enzyme activity deficits in GBA1-mutant PD. Levels of recessive PD gene proteins involved in mitochondrial quality control were increased in sporadic PD, but not enhanced by the additional macroautophagy deficits identified in GBA1-mutant PD. Collectively, this thesis demonstrates that ALP dysfunction occurs prior to the abnormal accumulation of α-synuclein in PD-affected brain tissue, and that specific dysregulation of CMA and mitochondrial quality control pathways is an early pathological event in sporadic PD that is not exacerbated by increased α-synuclein in later disease stages. GBA1 mutation-induced GCase deficits were related to additional macroautophagy dysfunction. These findings have important implications in the development of therapeutic strategies to restore PD-induced ALP deficits.
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Author(s)
Murphy, Karen
Supervisor(s)
Halliday, Glenda
Cooper, Antony
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Publication Year
2013
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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