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

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  1. 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!

  2. 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:

    . Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011 Aug 15;20(16):3207-12. PubMed.

  3. Stress granules are commonly induced by viruses, including herpes simplex, and there is a recent review on the process in PLoS Pathogens.

    References:

    . 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.

    . How do viruses interact with stress-associated RNA granules?. PLoS Pathog. 2012 Jun;8(6):e1002741. PubMed.

References

News Citations

  1. DC: What’s That New Stuff in and Around Nuclei of AD Cells?

Other Citations

  1. rTg4510

External Citations

  1. JNPL3

Further Reading

Papers

  1. . TDP-43 aggregation in neurodegeneration: Are stress granules the key?. Brain Res. 2012 Feb 22; PubMed.
  2. . 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.
  3. . Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. Neurobiol Aging. 2011 Dec;32(12):2323.e27-40. PubMed.

Primary Papers

  1. . Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 2012 Jun 13;32(24):8270-83. PubMed.