Project Summary:
Multiple system atrophy (MSA) affects over 2000 Australians. MSA is a distinct member of the group of neurodegenerative diseases called α-synucleinopathies whereby the fibrillar protein α-synuclein aggregates in brain tissue. Although well-defined clinically the molecular causes of MSA has not yet been elucidated. We recently discovered that hemoglobin genes are highly expressed in the MSA brain. Hemoglobin protein transports oxygen throughout our tissues. It is the largest source of peripheral iron in the human body and it may play a role in regulation of iron level in the brain. We hypothesize that the increased levels of hemoglobin cause oxidative stress, which leads to impairment of brain cells functionality. Moreover, oxidative stress, together with increased levels of hemoglobin proteins, might have a direct impact on α-synuclein aggregation.
This project employs comprehensive molecular analysis to discover a mechanism through which increased amounts of hemoglobin lead to MSA onset and progression. This ambitious goal will be achieved through determination of different cell types involved in MSA, physiological effects of hemoglobin overexpression in the brain and relationship between hemoglobin and α-synuclein deposits. This project, for the first time, will establish a link between MSA-specific neurodegeneration, iron levels and α-synuclein aggregation. This proposal is significant because it will not only provide insights into MSA disease mechanism but also will lead to identification of new molecular targets for MSA early diagnosis and therapeutic intervention.
Research Outcome:
The Brain Foundation Research Gift enabled us to discover that haemoglobin overexpression and alpha-synuclein aggregation is accompanied by a cellular response. In this project we have characterised this physiologic response of transgenic oligodendrocyte precursor cells to exposure to soluble and fibrillar alpha-synuclein using two-dimensional differential gel electrophoresis analysis. Using mass spectrometry (MS) we evaluated changes upon haemoglobin overexpression and alpha-synuclein exposure as well as assessed post-translational modifications as a result of alpha-synuclein aggregation. Principal component analysis of selected proteins of interest revealed that the differences between untreated control cells and cells exposed to soluble oligomeric alpha-synuclein are not significant. In contrast analysis of the protein spots from cells exposed to fibrillar alpha-synuclein showed significant difference as compared to control. Proteins which underwent expression changes upon exposure to exogenous alpha-synuclein fibrils, were identified using tandem MS. We identified proteins involved in regulation of transcription, DNA replication, cell signalling and regulation of translation.
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