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Investigation of the normal function of the brain protein p25alpha and its relation to demyelinating disorders

Ditte Maria Simonsen Lundvig  

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Accepted by: Faculty of Health Sciences University of Aarhus
Defended on: December 7, 2007
Official opponents: Niels Gregersen , Claus Oxvig , Niels A. Jensen
Tutors: Poul Henning Jensen , Daniel E. Otzen

Published in the PhD Database: November 23, 2007

English abstract
The PhD dissertation ¿Investigation of the normal function of the brain protein p25alpha and its relation to demyelinating disorders¿ is based on experimental work performed at the Institute of Medical Biochemistry, University of Aarhus. The work was conducted to gain further insight into the structural and functional aspects of the brain-specific protein p25alpha. The main results of this PhD study are presented in three separate scientific reports.
The brain-specific protein p25alpha co-localizes with insoluble alpha-synuclein aggregates in intracellular inclusions that are the pathological hallmark of a group of neurodegenerative disorders known as alpha-synucleinopathies. The aggregation and accumulation of -synuclein is known to be pivotal in the pathogenesis of the alpha-synucleinopathies. Importantly, p25alpha induces alpha-synuclein aggregation in vitro, suggesting that p25alpha may be a key player in the pathogenesis of these diseases. The p25alpha protein was identified more than a decade ago, yet its normal function as well as its putative role in pathogenesis of the alpha-synucleinopathies still is speculative.
Protein structure is closely related to function, and studies have reported the bovine p25alpha protein has an unfolded structure. Yet, we subjected recombinant human p25alpha to different spectroscopic techniques and chemical cross-linking studies, and found that p25alpha displays characteristics of a folded protein. However, p25alpha is rapidly digested by proteases and displays abnormal migration behaviour during analytical gel filtration. This suggests that p25alpha is a folded protein with a flexible and dynamic structure. The results have been published in Protein Science.
The second report describes the developmental expression profile of rat p25alpha. p25alpha has previously been reported to be a brain-specific protein with a postnatal expression pattern in rat. We confirm that p25alpha is a brain-specific protein and that its expression is detectable prenatally in myelinating oligodendrocytes. The results have been published in Journal of Neurochemistry.
The third study identifies myelin basic protein (MBP) as a novel binding partner of p25alpha. By immunohistochemistry, we demonstrate that MBP and p25alpha are colocalized in myelinated pontine fiber tracts, thereby identifying p25alpha as a novel component of the myelin sheath. Importantly, the colocalization of p25alpha and MBP is reduced in cases of multiple system atrophy (MSA), an alpha-synucleinopathy which is characterized by oligodendrocyte pathology. Here, p25alpha accumulates in the oligodendrocyte cell body, resulting in cellular expansion and occurrence of alpha-synuclein-containing inclusions. This suggests that p25alpha is involved in the pathology of MSA. These results have been published in American Journal of Pathology.
In conclusion, this PhD study provides new information on the function of p25alpha as well as its role in neurodegenerative disorders. These data may therefore contribute to the description of new pathogenic mechanisms that may be relevant for the development of new therapeutic strategies of alpha-synucleinopathies.

Danish abstract