AbstractTau is a microtubule associated protein found in inclusions in tauopathies including Alzheimer's disease. One known cause of neurodegeneration is an excess of exon 10 inclusion in tau mRNA which is caused by several mutations in the MAPT gene, encoding tau. Processing of the Amyloid Precursor Protein (APP) generates P- amyloid (Ap) peptides which are deposited as amyloid plaques in AD brain. APP transcripts containing alternatively spliced exon 7 are increased in AD brain and processing of APP exon 7 containing protein isoforms may result in increased AP production.
Recently, the DNA and RNA- binding protein, Tar DNA binding protein of 43 kDa (TDP-43) inclusions have been found in 20-35% of AD cases as well as other tauopathies. TDP-43 has roles RNA processing regulation including pre-mRNA splicing. Cytoplasmic inclusions ofTDP-43 result in a loss of nuclear TDP-43 and suggest a loss of TDP-43 function that may impair its role in multiple RNA processing events. Our hypothesis is that TDP-43 dysfunction affects tau and APP RNA processing either directly or indirectly. We analysed post-mortem from human brain tissue and found an increase in severity of tau pathology associated with the presence ofTDP-43 inclusions suggesting that TDP-43 dysfunction may modify tau pathology in AD brain. We found increased expression of tau exon 10 that correlated with increased expression of APP exon 7 in a subset of AD cases however there was no association between presence of TDP-43 inclusions and altered tau or APP splicing.
|Date of Award
|1 Nov 2013
|Jean-Marc Gallo (Supervisor) & Tibor Hortobagyi (Supervisor)