Neuroscientists focus much attention on long-lasting aggregates such as tangles and plaques, but they would do well to study transient gobs like stress granules also, according to Ben Wolozin of Boston University. In the June 13 Journal of Neuroscience, Wolozin and colleagues report how stress granules push tau to aggregate, and how tau, in turn, incites stress granule formation. The paper essentially ties the two into a feedback loop. Moreover, the research team found that tau co-immunoprecipitates with stress granule proteins, suggesting tau tangles and the granules are linked directly or in a complex.
First author Tara Vanderweyde reported some of these results at the Society for Neuroscience meeting in December (see ARF related news story). In mice expressing human mutant tau, stress granules grow larger and more numerous over time. The team described three different “flavors” of granules, Wolozin said. They have different tendencies to colocalize with tau. Early on, tau lines up with stress granules containing the RNA binding protein T cell internal antigen-1 (TIA-1). As disease becomes more severe, tau associates with tristetraprolin (TTP)-labeled granules. In contrast, stress granules containing ras-GTPase-activating protein SH3 domain-binding protein (G3BP) are only rarely near tau. This pattern held true not only in tauopathy model mice, but also in autopsy tissue from six people who had Alzheimer’s disease.
The new data published today reflect how Vanderweyde further examined the interaction between stress granules and tau. She made whole brain lysates from severely ill tauopathy mouse strains JNPL3 and rTg4510, which both express human tau with the P301L mutation. TIA-1 and TTP co-immunoprecipitated with tau and with phosphorylated tau. To examine the interaction between TIA-1 and tau in vivo, Vanderweyde transfected human neuroblastoma SH-SY5Y cells with one or both and stressed the cells with arsenite. Excess TIA-1 boosted the numbers of tau inclusions, and vice versa. Both together increased the formation of stress granules and tau inclusions even further, and in many aggregates, tau and TIA-1 overlapped. “Since TIA-1 and TTP bind phospho-tau, and TIA-1 overexpression induces formation of phospho-tau inclusions, the data presented here suggest that stress granules might stimulate tau pathology,” wrote John Trojanowski of the University of Pennsylvania in Philadelphia, who was not involved in the study, in an e-mail to ARF (see full comment below).
Vanderweyde also found that, as in the Alzheimer’s cases, stress granules associated with tau in samples from five people who had tau mutations that cause frontotemporal dementia with parkinsonism (FTDP-17). “I think the massive stress granule response you get in AD and frontotemporal dementia is a response to the tauopathy,” Wolozin said. Stress granule proteins such as TIA-1 might be good biomarkers for neurodegeneration, he suggested, and treatments to dissolve stress granules could be therapeutic.
“These results make an important contribution to our understanding of the emerging role of stress granule pathways in neurodegenerative diseases,” wrote Aaron Gitler of Stanford University in Palo Alto, California, in an e-mail to ARF (see full comment below). “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,” added Gitler, who was not involved in the study.—Amber Dance
- Dewey CM, Cenik B, Sephton CF, Johnson BA, Herz J, Yu G. TDP-43 aggregation in neurodegeneration: Are stress granules the key?. Brain Res. 2012 Feb 22; PubMed.
- Castellani RJ, Gupta Y, Sheng B, Siedlak SL, Harris PL, Coller JM, Perry G, Lee HG, Tabaton M, Smith MA, Wang X, Zhu X. A novel origin for granulovacuolar degeneration in aging and Alzheimer's disease: parallels to stress granules. Lab Invest. 2011 Dec;91(12):1777-86. PubMed.
- Gal J, Zhang J, Kwinter DM, Zhai J, Jia H, Jia J, Zhu H. Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. Neurobiol Aging. 2011 Dec;32(12):2323.e27-40. PubMed.
- 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.