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.