Single molecule profiling of tau gene expression in Alzheimer's disease.
Tau is a microtubule-associated protein that is important for establishing and maintaining neuronal morphology. In addition to its role in normal cells, tau protein is involved in many neurodegenerative diseases, e.g. Alzheimer's disease (AD) and frontotemporal dementia, as the main component of intraneuronal aggregates. Alternative splicing of tau gene in the brain can give rise to at least six protein variants. A causative role of skewed tau exon 10 inclusion has been defined in frontotemporal dementia; however, no link was established between the aberrant splicing of tau and AD. Here, we applied a single-molecule-based technology, polymerase colony or polony, to simultaneously monitor tau splicing variant and haplotype profile in sporadic AD and normal brains. We found that the coordinated expression of tau exons 2 and 10 is altered in AD. Additional investigations of cis and trans mechanisms of this observation revealed a decreased protein expression of a known tau splicing factor, htra2-beta-1 in AD, thereby implicating a trans mechanism. Our results demonstrate that dysregulation of combinatorial splicing might serve as a signature for aging-related diseases, and the polony assay could be widely adapted for the study of other tauopathies. Furthermore, splicing-based therapeutics is an emerging area of drug development, and a well-defined and quantitative assay for monitoring single-gene transcriptome will be relevant for such development.
Conrad
Chris
C
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease (MIND), Charlestown, Massachusetts, USA. cgc2105@columbia.edu
Zhu
Jun
J
Conrad
Cintia
C
Schoenfeld
David
D
Fang
Zhide
Z
Ingelsson
Martin
M
Stamm
Stefan
S
Church
George
G
Hyman
Bradley T
BT
D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics*; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D001681:Biological Assay / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D005091:Exons / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D008967:Molecular Biology / Q000379:methods; D020033:Protein Isoforms / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D016875:tau Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2