Functional genomics dissects pathomechanisms in tauopathies: mitosis failure and unfolded protein response.
BACKGROUND
Alzheimer's disease (AD) is characterized by beta-amyloid (Abeta) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of Abeta(42), both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, Abeta(42) induces tau aggregation. While both Abeta(42) and mutant tau cause neuronal dysfunction, their modes of action are only vaguely understood.


METHODS
To determine which processes are disrupted by Abeta(42) and/or P301L mutant tau, we used transcriptomic and proteomic techniques followed by functional validation and analysis of human AD tissue.


RESULTS
Our transcriptomic study in the SH-SY5Y cell culture system revealed that Abeta(42) and P301L tau expression independently affect genes controlling the cell cycle and cell proliferation. Proteomics applied to Abeta(42)-treated P301L tau-expressing SH-SY5Y cells and the amygdala of Abeta(42)-injected P301L transgenic mice revealed that a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. Among the proteins identified was valosin-containing protein (VCP), a component of the quality control system during endoplasmic reticulum stress. Mutations in VCP have recently been linked to frontotemporal dementia.


CONCLUSIONS
Our data support the mitosis failure hypothesis that claims that aberrant cell cycle reentry of postmitotic neurons induces apoptosis. Furthermore, our data underline a role of Abeta(42) in the stress response associated with protein folding.
Götz
Jürgen
J
Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, NSW, Australia. jgoetz@med.usyd.edu.au
David
Della
D
Hoerndli
Frederic
F
Ke
Yazi D
YD
Schonrock
Nicole
N
Wiesner
Andreas
A
Fath
Thomas
T
Bokhari
Laita
L
Lim
Yun-An
YA
Deters
Natasha
N
Ittner
Lars M
LM
D000818:Animals; D023281:Genomics / Q000379:methods; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D017510:Protein Folding; D024801:Tauopathies / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics
D016875:tau Proteins