The formation of cytoplasmic inclusions called stress granules is one of nature’s many ways of coping with adverse situations. It appears that these inclusions sequester non-essential messenger RNAs, allowing cells to focus on making proteins, such as chaperones, that protect against a variety of stressful insults. Recent work suggests that stress granules may figure in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, where stress granule markers decorate pathological protein aggregates in affected neurons. What do stress granules do in disease? Are they part of the problem or part of the solution? What about AD?
TDP-43 in stress granules
|Image caption: In human neuroblastoma cells transfected with TDP-43, inclusions (arrows) test positive for both TDP-43 (green) and the stress granule marker TIA-1 (red).
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This Webinar on stress granules and their relevance to neurodegeneration was led by Ben Wolozin, Boston University; Daryl Bosco, University of Massachusetts Medical Center, Worcester; and Dorothee Dormann, Ludwig-Maximilians-University, Munich, Germany. Aaron Gitler, University of Pennsylvania, Philadelphia, joined them for a panel discussion.
Never heard of stress granules? Not to worry; they are new to the neurodegeneration scene, and that is why we are featuring them in this discussion. Stress granules are cytoplasmic inclusions of proteins that play key roles in translation of messenger RNA. They form naturally when a cell deals with stress, such as heat shock, oxygen deprivation, or oxidative damage. They can also be experimentally induced by knocking down (Mokas et al., 2009) or inhibiting (Kedersha et al., 1999) key translation factors, or by overexpressing proteins or adding drugs that block translation (Dang et al., 2006; Mazroui et al., 2006). The precise role of stress granules is unclear, but one theory is that they sequester mRNA transcripts that are not used in coping with stress (see Anderson and Kedersha, 2008). Stress granules dissipate when the stress has passed, and their disassembly correlates with the resumption of general protein synthesis (Mazroui et al., 2007).
These granules contain many of the proteins that are involved in translation, including ribosomal subunits and translational initiation factors such as eukaryotic initiation factors 2, 3, and 4. They also contain polyA mRNA and polyA binding proteins (for a review, see Anderson and Kedersha, 2006) and other components that seem to recruit mRNA to the granules, such as T cell intracellular antigen 1 (TIA-1) and RasGAP-associated endoribonuclease (G3BP). Proteins implicated in neurodegenerative or neurologic diseases have also been linked to these bodies. Ataxin-2, which causes a form of spinocerebellar ataxia when mutated, and survival motor neuron (SMN), the protein at the root of spinal muscular atrophy, both disrupt stress granule formation (Nonhoff et al., 2007; Hua and Zhou, 2004). SMN binds to stress granule proteins, as does huntingtin (Waelter et al., 2001) and prion protein (Goggin et al., 2008). There also seems to be a link between stress granules and the fragile X mental retardation protein (FMRP), whose normal role is to repress translation of RNA in dendrites. FMRP associates with RNAs and proteins found in stress granules (Vanderklish and Edelman, 2005; Linder et al., 2008), and mutations in FMRP protein that cause fragile X syndrome also disrupt these inclusions (Didiot et al., 2008).
More recently, researchers linked stress granules to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Wolozin and colleagues reported that the RNA-binding protein TDP-43 gets incorporated into stress granules (see ARF related news story on Liu-Yesucevitz et al., 2010). TDP-43 mutations have emerged as a cause of a small subset of familial ALS cases and some cases of frontotemporal dementia, and aggregates of the protein occur in a majority of ALS cases studied on autopsy. TDP-43 appears to interact with TIA-1, both directly and via RNA. In postmortem tissue from people with ALS and FTLD-U, TDP-43 also colocalizes in inclusions containing TIA-1 and eukaryotic initiation factor 3, suggesting that the TDP-43 inclusions formed in these diseases are stress granules. Interestingly, Gitler and colleagues reported that ataxin-2, normally associated with ataxia, increases a person’s risk for ALS when it undergoes a moderate polyglutamate expansion (Elden et al., 2010). Since ataxin-2 binds stress granules, this strengthens the link between those inclusions and ALS.
Further support for the involvement of these granules in ALS comes from Bosco’s lab and also from Christian Haass’ lab at Ludwig-Maximilians-University, Munich, Germany. Both found that mutants of another RNA binding protein that causes familial ALS, fused in sarcoma (FUS), also end up in stress granules (Dorman et al., 2010 and Bosco et al., 2010). Bosco’s group in collaboration with Larry Hayward, also at UMass Medical Center, found that in cell and zebrafish models of ALS, FUS is more likely to end up in these granules when the scientists apply additional stress, for example, heat shock or oxidative damage.
How do these stress granules fit in with the pathology of ALS/FTLD? Do mutants of TDP-43 and FUS simply make cells more vulnerable to stress, or is there more to the story? What about other neurodegenerative diseases, for example, Alzheimer’s?
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