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Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 2012 Jun 13;32(24):8270-83. PubMed.
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University of Pennsylvania
The Wolozin group investigates stress granules (SGs) because stress has been shown to induce aggregation of RNA-binding proteins to form SGs. Hence, the researchers asked if SG proteins colocalize with Alzheimer's disease signature lesions, i.e., neurofibrillary tangles and amyloid plaques. To that end, they examined the relationship between SG proteins and neuropathology in the brains of P301L tau transgenic mice, and cases of Alzheimer's disease (AD), as well as in subjects with the autosomal familial tauopathy known as FTDP-17. The pattern of SG pathology differs dramatically based on the RNA-binding proteins 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, the ras GAP-binding protein known as G3BP identified a novel pathology that increased in neurons as disease severity increased, but often, this was not associated with tau pathology. Since TIA-1 and TTP bind phospho-tau, and TIA-1 overexpression induces formation of phospho-tau inclusions, the data presented here suggest that SGs might stimulate tau pathology. These data prompt the authors to conclude that further studies of RNA-binding proteins and SG biology may provide new avenues for identifying novel mechanisms that regulate tau biology. The studies described here are interesting but preliminary efforts to interrogate the potential role of RNA-binding proteins and SG biology in mechanisms of AD. The next chapter in this story is awaited with great expectations!
View all comments by John TrojanowskiStanford University
This manuscript presents a comprehensive analysis of stress granule pathology in mouse models of tauopathies and in postmortem tissue from Alzheimer's disease patients. An important role for defects in RNA metabolism in general, and stress granule pathology in particular, has been established for the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). However, it was unclear if similar pathologies are associated with neurodegenerative diseases involving tau (e.g., FTLD-tau or Alzheimer's disease).
Wolozin and colleagues find a dramatic increase in stress granule (SG) formation as their mouse tauopathy models progress from early to moderate to severe disease stages. Interestingly, they also see marked colocalization of tau pathology with SG proteins.
Convincingly, they show directly that inducing stress granules promotes tau pathology and vice versa. In my opinion, these results make an important contribution to our understanding of the emerging role of stress granule pathways in neurodegenerative diseases. Furthermore, this study provides a valuable resource for the neurodegenerative disease community, because it presents a detailed description of the emergence and development of stress granules in brain regions affected by pathological tau accumulation.
Ataxin-2 has previously been connected to neurodegenerative diseases SCA2 and ALS. In a recent study, Rademakers and colleagues observed ataxin-2 polyglutamine expansions in a neurodegenerative disease tauopathy called progressive supranuclear palsy (Ross et al., 2011). Since ataxin-2 is also a critical regulator of SGs, this might be an additional mechanistic connection among tau, SGs, and disease.
References:
Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM, Dejesus-Hernandez M, Adamson J, Li M, Volkening K, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Woodruff BK, Knopman DS, White CL, Van Gerpen JA, Meschia JF, Mackenzie IR, Boylan K, Boeve BF, Miller BL, Strong MJ, Uitti RJ, Younkin SG, Graff-Radford NR, Petersen RC, Wszolek ZK, Dickson DW, Rademakers R. Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011 Aug 15;20(16):3207-12. PubMed.
View all comments by Aaron GitlerPolygenicPathways
Stress granules are commonly induced by viruses, including herpes simplex, and there is a recent review on the process in PLoS Pathogens.
References:
Esclatine A, Taddeo B, Roizman B. Herpes simplex virus 1 induces cytoplasmic accumulation of TIA-1/TIAR and both synthesis and cytoplasmic accumulation of tristetraprolin, two cellular proteins that bind and destabilize AU-rich RNAs. J Virol. 2004 Aug;78(16):8582-92. PubMed.
Lloyd RE. How do viruses interact with stress-associated RNA granules?. PLoS Pathog. 2012 Jun;8(6):e1002741. PubMed.
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