Public examination of a doctoral dissertation in the field of molecular medicine
Doctoral candidate: MSc Jayashree Viswanathan
Time and venue: 17.6.2011 at 12 noon, Medistudia Auditorium ML1, Kuopio campus
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world that typically begins after the age of 65 years. The prevalence of AD rises to approximately 50% among people above the age of 85. The main symptoms of AD are memory impairment along with deterioration in cognitive and language skills. These symptoms result from death of nerve cells, or neurodegeneration, in brain areas that are responsible for memory formation and cognitive abilities. This neurodegeneration is a slow process which takes decades. Advancements in genetic technologies have led to the identification of several candidate genes that affect the risk of developing AD, but the exact molecular mechanisms behind their effects are still poorly known. This thesis looks at the genetic and functional contribution of specific risk genes to the pathogenesis of AD.
Mutations in the amyloid precursor protein (APP) gene are known to cause AD. Duplications in the APP gene locus have been previously reported in French and Dutch AD patients. The duplication leads to three copies of APP as opposed to the normal two copies. This increased gene load leads to earlier onset of AD. In study I of this thesis, we screened Finnish AD patients for APP duplications, but found none. Our results thus suggest that APP duplications are rare in the Finnish population.
Mutations in the granulin (GRN) gene cause frontotemporal dementia, the second most common early onset dementia after AD. Certain variations in GRN also increase the risk for AD. In study II, we assessed the role of GRN in the susceptibility to AD. Our analysis using single nucleotide polymorphisms (SNPs) indicated that GRN might play a role in AD susceptibility in a gender-specific manner.
In studies III and V we focused on ubiquilin-1 which is genetically and functionally associated with AD. Ubiquilin-1 also mediates the proteasomal degradation of several proteins, such as presenilin-1 (PS1). PS1 is the catalytic subunit of the γ-secretase enzyme complex, a key enzyme in AD pathogenesis. Ubiquilin-1 has four transcript variants (TVs), which are produced by alternative splicing of the ubiquilin-1 mRNA. In study III, we assessed the role of ubiquilin-1 TVs on PS1 protein aggregation. We found that ubiquilin-1 TV1, and even more prominently TV3, caused accumulation of PS1 into aggresomes. Aggresomes are cytoplasmic inclusions containing aggregated proteins. Furthermore, we found evidence that the aggresomes are cleared from the cells by autophagocytosis. Our results suggest that ubiquilin-1 targets excess PS1 to the proteasome for degradation or alternatively to the aggresomes. Since TV3 lacks an essential domain required for interaction with the proteasome, it is unable to efficiently mediate proteasomal degradation of PS1. Therefore, TV3 targets accumulated PS1 to the aggresomes. These findings along with current literature regarding the role of ubiquilin-1 in protein aggregation and aggresome formation are summarised in the review article III included in the thesis.
Study V investigated the role of ubiquilin-1 TVs in APP processing and γ-secretase function, two central events in AD pathogenesis. We found that TV1 increases APP maturation and processing, and modulates γ-secretase activity, through independent mechanisms. TV2, which is genetically associated with increased risk for AD, also alters APP processing but does not modulate γ-secretase activity. These differences could be the result of structural differences between the two TVs, suggesting that alternative splicing may regulate ubiquilin-1 function in AD pathogenesis
This thesis provides new genetic and functional information on the effects of specific known and novel risk genes and their relationships in AD pathogenesis. These findings increase our understanding of the potential underlying molecular mechanisms involved in AD pathogenesis and may help in the identification of novel therapeutic targets for treating AD.
The doctoral dissertation of Master of Science Jayashree Viswanathan, entitled Genetic and Functional Characterization of Alzheimer's Disease-Associated Genes will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Henrik Zetterberg of the University of Gothenburg and the custos will be Docent Mikko Hiltunen of the University of Eastern Finland..
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Publishing year: 2011Back to this years article listing