Understanding the role of ATP13A2 in endo-lysosomal pathways
AffiliationFlorey Department of Neuroscience and Mental Health
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2021-03-25.
© 2018 Dr Mathew Chiam
Parkinson’s disease (PD) is a common neurodegenerative disease affecting 1 to 2% people aged over 65. Cytoplasmic inclusions are pathognomonic of PD and point to dysregulation of protein clearance as a central part of the pathology. Two forms of familial PD result from mutations in the genes for the ATP13A2 and α-synuclein proteins. One of these proteins (α-synuclein) forms the characteristic inclusions of PD and is thus likely to be affected by dysregulated protein clearance, whereas the other is part of the endo-lysosomal system (ELS), which is a central component of protein clearance. The predictions on which these studies were based on were that removal of ATP13A2 would have i) a deleterious effect on ELS function; ii) induce aspects of neurodegeneration; iii) dopaminergic systems would be most susceptible; iv) the presence of high levels of α-synuclein would exacerbate these changes. None of these proved correct in these mice and instead it appears that removal of ATP13A2 results in i) improved capacity of ELS function; ii) there is no loss of neurons but there is neuro gliosis; iii) there is plasticity in the dopaminergic systems that suggest a response to altered neurotransmission; iv) the presence of high levels of α-synuclein did not exacerbate any aspect of the pathology and the absence of ATP13A2 in the presence of increased α-synuclein expression resulted in improved clearance of α-synuclein. These unexpected findings open up several new avenues for investigation of the normal physiological role of these proteins in the ELS and also for investigating whether understanding the mechanisms of the improved α-synuclein clearance might reveal new therapeutic targets for protein clearance disorders.
Keywordsalpha synuclein; ATP13A2; PARK9; ELS; autophagy; endocytosis; dopaminergic
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