Newest ALS/FTD Gene Keeps Spotlight on Stress Granules

In the August 16 Neuron, researchers led by Rosa Rademakers, Mayo Clinic, Jacksonville, Florida, and Paul Taylor, St. Jude Children’s Research Hospital, Memphis, Tennessee, report that mutations in the gene TIA1 cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Their study hits a familiar refrain: Like several other ALS genes, TIA1 encodes an RNA-binding protein found in stress granules. Mutations in TIA1 impair stress granule function and promote the accumulation of toxic TDP-43, a hallmark of the diseases, the researchers find.

Persistent Granules.
HeLa cells that express A381T TIA1 (bottom) have more stress granules (bright green) at 80 minutes (left) and 120 minutes (right) after heat shock than do control cells (top). [Courtesy of Rosa Rademakers and Neuron.]

TIA1 joins a growing list of RNA-binding proteins that instigate neurodegeneration leading to ALS/FTD, reinforcing the central role of stress granules in that process. Alzforum covered part of the work when Taylor presented it earlier this year at a meeting on liquid-liquid phase transition in Leuven, Belgium (see May 2017 conference news).

Rademakers and Taylor collaborated with Ian Mackenzie’s group at the University of British Columbia, Vancouver, Canada. Co-first authors Mackenzie, Alexandra Nicholson, and Mohona Sarkar in Rademakers’ lab first uncovered a potential role for TIA1 in a family with multiple cases of ALS and FTD, and no known disease-causing mutations. Sequencing of all the protein coding genes of two affected members—a woman and her niece—found that they shared rare mutations in 15 genes. A missense variant in TIA1, P362L, stood out. First, TIA1 structurally and functionally resembles other ALS disease genes, such as TDP-43, hnRNPA1, and FUS, and mutations in all these affect protein aggregation in stress granules, where TIA1 localizes. Second, the P362L mutation sat in the prion-like tail of the protein, a region of low amino acid complexity. Low-complexity domains (LCD) play a critical role in protein phase transitions that spark stress granule formation (see March 2017, October 2015 news; Kato et al., 2012). Last but not least, a TIA1 mutation in the LCD was known to cause a proteinopathy in the form of Welander distal myopathy, a muscle-wasting disease that features TDP-43 aggregates.

Deciding to focus on TIA1, the investigators sequenced the gene in 1,039 other cases of ALS and 3,036 healthy controls. In six patients they found five additional mutations in the TIA1 LCD domain. None of these turned up in healthy controls. The researchers believe the TIA1 mutations are pathogenic and based on these numbers, Rademakers estimates that they could account for one in 50 cases of familial, and as many as one in 200 cases of sporadic ALS, on par with other rare ALS/FTD genes such as VCP and profilin. TIA1 joins a growing list of genes that cause multisystem proteinopathies, striking the nervous system, muscle, or bone.

Carriers of TIA1 mutations shared a special type of pathology. In five cases for which there were autopsy results, the investigators found unusually large, round, and dense TDP-43 inclusions in motor neurons. These “huge” lesions can be found in sporadic ALS, but rarely, said Rademakers. “All of our five patients had them and they had a lot of them,” she told Alzforum. This shared pathology convinced her that the scientists had in fact discovered a new genetic cause of ALS/FTD.

Taylor’s group then analyzed the effects of two of the TIA1 ALS mutations, P362L and A381T, and the E384K distal myopathy mutation, on protein behavior in vitro. All three altered the biophysical properties of the protein, increasing its propensity to undergo liquid-liquid phase separation in vitro. Scientists believe phase separation precedes stress granule formation. While the mutations did not affect stress granule assembly in cells in response to heat shock, after that stress passed the stress granules formed with mutant protein hung around much longer than those that incorporated wild-type TIA1. In addition, TDP-43 recruited to the persistent stress granules rapidly became immobile and insoluble, suggesting a means whereby the mutants promote TDP-43 aggregation and neurodegeneration.

“It’s particularly interesting that disease-causing mutations promoted phase separation. ALS-associated mutations in other genes don’t. They promote fibril formation, which we think is a later step in the process,” said Lindsay Becker, a doctoral student in the lab of Aaron Gitler at Stanford University. “This provides good evidence that phase separation is involved in ALS.”

Featured Paper

Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, Matchett BJ, Mittag T, Temirov J, Hsiung GR, Krieger C, Murray ME, Kato M, Fryer JD, Petrucelli L, Zinman L, Weintraub S, Mesulam M, Keith J, Zivkovic SA, Hirsch-Reinshagen V, Roos RP, Züchner S, Graff-Radford NR, Petersen RC, Caselli RJ, Wszolek ZK, Finger E, Lippa C, Lacomis D, Stewart H, Dickson DW, Kim HJ, Rogaeva E, Bigio E, Boylan KB, Taylor JP, Rademakers R. TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron. 2017 Aug 16;95(4):808-816.e9.[PubMed].

Further Reading

McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, Rouleau GA, Vande Velde C. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet. 2011 Apr 1;20(7):1400-10. [PubMed].

Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, Anderson P. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell. 2004 Dec;15(12):5383-98. [PubMed].

Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, McKnight SL. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell. 2012 May 11;149(4):753-67. [PubMed].

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aggregation ALS/FTD disease-als disease-ftd liquid-liquid phase transition stress granules tdp-43 TIA1 topic-genetics topic-preclinical
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