TIA1 has a toxic relationship with tau. Toxic to neurons, that is. In the November 20 Nature Neuroscience, researchers led by Benjamin Wolozin of Boston University reported that the RNA-binding protein has a penchant for tau oligomers, stabilizing them and slowing their transformation into neurofibrillary tangles. Halving the expression of TIA1 in tau-transgenic mice lessened synaptic deficits, protected neurons, preserved memory, and prolonged the animals’ lives. The findings place TIA1, and potentially other RNA-binding proteins, at the scene of tau-mediated neurodegeneration, and support the idea that oligomers, rather than tangles, are the most noxious form of tau.
- In vitro, TIA1 stunts tau fibril growth, stabilizes tau oligomers.
- In PS19 mice, the protein preferentially associates with oligomers.
- Reducing TIA1 promoted tau tangles and reduced toxicity.
Wolozin presented the bulk of the findings at the Phase Transitions in Biology and Disease meeting held last May in Leuven, Belgium (May 2017 conference news). There, and in the paper, the researchers reported that TIA1, which facilitates the formation of membraneless organelles called stress granules, plays a hand in neuronal damage in PS19 mice. These animals overexpress the P301S mutant tau that causes frontotemporal dementia, and suffer losses in synapses and neurons by six months of age. However, PS19 animals with half as much TIA1 mustered normal numbers of hippocampal and cortical neurons even at nine months old. At that age the animals performed at wild-type levels on the Y-maze and novel-object-recognition tests, and they lived an average of two months longer than animals with both copies of TIA1. Curiously, TIA1-deficient animals benefitted despite having more neurofibrillary tangles in their brains than PS19 controls.
The paper dives deeper into the biochemical relationship between TIA1 and tau. First author Daniel Apicco and colleagues reported that in PS19 mice, tau oligomers co-aggregate with TIA1, as well as other RNA-binding proteins. In animals deficient in TIA1, RNA-binding proteins associated less with tau oligomers, suggesting that TIA1 plays a pivotal role in initiating these interactions. Reducing TIA1 also delayed the appearance of phosphorylated tau in the hippocampus, but doubled the amount that eventually accumulated there. Notably, Apicco found that TIA1 stymied the growth of tau fibrils in vitro, yet promoted the formation of smaller oligomers. Electron microscopy revealed that fibrils were stunted when TIA was present, and showed TIA1 and tau closely associating.
How does all this help explain tau pathology? Wolozin proposed that under conditions of cellular stress, tau becomes phosphorylated shortly after it is made in the somatodendritic compartment and starts to oligomerize. Then, instead of travelling to axons to stabilize microtubules, this toxic form of tau associates with TIA1 and RNA in stress granules. This jibes with recent findings that tau undergoes liquid-liquid phase separation, and that both RNA and phosphorylation of tau promote this transition (Jul 2017 news; Aug 2017 news). TIA1’s interaction with tau would then stabilize these damaging tau oligomers, he proposed.
Aaron Gitler of Stanford University in California was intrigued by the apparent influence of TIA1 on tau phosphorylation and oligomerization, and noted that the results were convincing. “A role for stress granules now extends to tauopathies, and TIA1 may represent a new therapeutic target,” he wrote to Alzforum.
Jose Abisambra of the University of Kentucky in Lexington agreed, pointing out that TIA1 could play a broad role in pathogenesis of other neurodegenerative diseases where liquid droplet abnormalities have been implicated, including amyotrophic lateral sclerosis and frontotemporal dementia. “The fact that knockdown, and not knockout, of TIA1 offered neuroprotection gives hope that chemical targeting of TIA1 could offer benefits to patients suffering from these devastating disorders without complete ablation of TIA1,” he wrote to Alzforum. —Jessica Shugart
- Protein Liquid-Liquid Phase Transitions: The Science Is About to Gel
- Tau Hooks Up with RNA to Form Droplets
- More Droplets of Tau
Research Models Citations
- Li YR, King OD, Shorter J, Gitler AD. Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013 Apr 29;201(3):361-72. PubMed.
- Maziuk B, Ballance HI, Wolozin B. Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders. Front Mol Neurosci. 2017;10:89. Epub 2017 Apr 4 PubMed.
- Apicco DJ, Ash PE, Maziuk B, LeBlang C, Medalla M, Abdullatif AA, Ferragud A, Botelho E, Ballance HI, Dhawan U, Boudeau S S, Cruz AL AL, Kashy D, A, Goldberg LR, Yazdani N, Zhang C, Ung CY, Tripodis Y, Kanaan NM, Ikezu T, P, Leszyk J, Hu H, Luebke J, Bryant CD, Wolozin B. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci Nov. 20, 2017