Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies.
Stress induces aggregation of RNA-binding proteins to form inclusions, termed stress granules (SGs). Recent evidence suggests that SG proteins also colocalize with neuropathological structures, but whether this occurs in Alzheimer's disease is unknown. We examined the relationship between SG proteins and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer's disease and FTDP-17. The pattern of SG pathology differs dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially do not colocalize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology. Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD, providing potentially new avenues for identifying diseased neurons and potentially novel mechanisms regulating tau biology.
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA.
Tara
T
Vanderweyde
Haung
H
Yu
Megan
M
Varnum
Liqun
L
Liu-Yesucevitz
Allison
A
Citro
Tsuneya
T
Ikezu
Karen
K
Duff
Benjamin
B
Wolozin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000473:pathology*; D004265:DNA Helicases; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D039102:Poly(A)-Binding Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D021381:Protein Transport; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D000074019:T-Cell Intracellular Antigen-1; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D051816:Tristetraprolin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D002352:Carrier Proteins; C054369:MAPT protein, human; D039102:Poly(A)-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D051816:Tristetraprolin; D016875:tau Proteins; D004265:DNA Helicases; C116070:G3BP1 protein, human; C492055:G3bp1 protein, mouse; D020365:RNA Helicases