03 Mar 2020

Tau2020, a new international conference on all things—you guessed it—tau, unfolded in Washington, D.C, February 12 to13. This open meeting grew out gatherings of the Tau Consortium held in previous years, which were funded by the Rainwater Charitable Foundation and were closed to the public. Tau2020 was larger, drawing 650 researchers from 21 countries, and was co-organized by RCF, the Alzheimer’s Association and CurePSP. Unlike other conferences, Tau2020 covered all tauopathies, including Alzheimer’s disease, Progressive Supranuclear Palsy (PSP), frontotemporal dementias, and Pick’s disease. “I see this meeting as an inflection point in tau biology,” Gil Rabinovici, University of San Francisco, told Alzforum. “It brought together researchers studying AD with those studying primary tauopathies and got them thinking outside their own silos.”

The Rainwater foundation has poured $100 million into tau research since its founder Richard Rainwater was diagnosed with PSP in 2009. “Tau2020 grew from a desire to partner with other groups committed to sharing ideas and moving the science forward,” said Diana Kerwin from the Kerwin Research Center, a private clinic in Dallas. Kerwin was Rainwater’s geriatrician before his passing in 2015. She co-led the Tau2020 program committee with Peter Davies, Albert Einstein College of Medicine, Manhasset, New York.

The meeting touched on most aspects of tau biology, from genetics and protein structure to toxicity, biomarkers, imaging, and therapeutics. An all-plenary format and plenty of time for panel discussions ensured lively debate. Scientists presented new data at this meeting. There were high-resolution cryoEM structures of α-synuclein, a newly discovered receptor for tau that might facilitate cell-to-cell transmission, PET pinpointing a region of proposed earliest tau deposition in AD, and human data on how well PET ligands image tau in non-AD tauopathies.

The biggest genetic news came courtesy of Edwin Jabbari and Huw Morris, University College London. They described a collaborative search for variants that influence PSP progression. To their surprise, their one hit landed near LRRK2, broadening this gene’s rap sheet beyond Parkinson’s disease.

Previously Jabbari and Morris had identified polymorphisms near the TRIM11/17 locus that associate with clinical subtypes of PSP (Nov 2018 conference news). These phenotypes include Richardson syndrome and the even less common, non-Richardson forms of PSP, such as PSP-Parkinsonism (PSP-P) and pure akinesia with gait freezing (PAGF).

Of those, Richardson syndrome progresses fastest. Its median duration is six to seven years, while people with PSP-P and PAGF generally survive for around nine and 13 years, respectively. Researchers are trying to develop therapeutics to slow progression of PSP. Morris wondered if genetic variants that influence progression might point to drug targets.

To find out, Jabbari and colleagues ran a survival genome-wide association study (GWAS) of a combined 1,001 people from a clinical and a postmortem cohort. The former came from the Progressive Supranuclear Palsy-Cortico-Basal Syndrome-Multiple System Atrophy (PROSPECT) study in the U.K.; the postmortem samples came from brain banks in the U.K., U.S., and Germany. PROSPECT analyzes brains upon death, hence more than 90 percent of people in both cohorts had a neuropathology-confirmed diagnosis.

None of the previously identified PSP risk genes, including TRIM11/17, MAPT, MOBP, EIF2AK3, and STX6, correlated with progression. That said, in the survival GWAS, one significant association emerged, at rs2242367. It slowed progression a bit. At this locus GG, AG, and AA genotypes correlate with 7.7, 6.9, and 6.6 years survival, respectively.

How might rs2242367 slow PSP? The SNP sits in intron 3 of the gene SLC2A13. It also lies only190 Kb away from rs76904798, a common variant near the LRKK2 gene that has been linked to Parkinson’s disease. Does rs2242367 affect SLC2A13 or is it a proxy for some co-inherited LRRK2 variant? The authors found no coding variants that fit either bill. Therefore, to figure out how this genetic polymorphism influences progression of PSP, the authors looked to gene expression. They searched databases that match expression changes of specific genes with variants, aka expression quantitative trait loci (eQTL), that correlate with those changes.

Jabbari turned to two eQTL datasets—the eQTLGEN whole-blood dataset of 32,000 samples, and a BRAINEAC eQTL dataset of about 120 samples. The former comprises data from 37 different projects worldwide, including the Framingham Heart and the Rotterdam Studies. BRAINEAC, aka, the U.K. Brain Expression Consortium, studies expression regulation in up to 12 different brain regions sampled from people who died without any sign of neurodegenerative disease. Jabbari discovered that, in eQTLGEN, rs2242367 alleles correlated with expression of two long, noncoding RNAs and also with expression of LRRK2, but not SLC2A13. Among 120 samples in the BRAINEAC eQTL dataset, there also was a correlation with LRRK2 expression, but it fell short of statistical significance. Among BRAINEAC samples of frontal cortex, putamen, and substantia nigra, the AG and GG genotypes, which correlated with longer survival, trended toward reduced LRRK2 expression. Whether the long coding RNAs may play any role in disease needs to be determined. “We still have a lot of work to do to understand this data,” said Morris.

Which is more important for a person’s PSP risk then, the blood or the brain? Morris said his study lacked power to detect significant expression differences in the brain, but he thinks changes there might be more important. However, he did not discount peripheral mechanisms. The variant could affect blood-derived cells that enter the brain, or remotely affect microglia in the brain. Jabbari told Alzforum that he plans to analyze single-cell eQTL data to see if it points to LRRK2 expression in specific brain cells.

This new data pleased Mark Cookson, National Institute on Aging, Bethesda, Maryland, who collaborated on the study and co-authored the paper now uploaded to bioRxiv. Cookson believes it could speed up clinical development of LRRK2 kinase inhibitors. “I think this [variant] is a big deal,” he told Alzforum. “If it can be confirmed, then it opens up LRRK2 kinase inhibitors to a broader population of patients, including some with very short survival. This would make clinical trial readouts shorter than looking for slower progression rates in PD,” he said. Cookson believes this could be a “game changer” if such a trial finds a sponsor.

Pfizer, Merck, Glaxo-SmithKline, Genentech, and Biogen have all LRRK2 programs. Denali Therapeutics has LRRK2 kinase inhibitor in Phase 1 clinical trial for Parkinson’s disease. Jabbari told Alzforum that while he is gathering data for replication studies, he has also already contacted companies to collaborate on PSP trials.

Tau sub haplotypes and primary tauopathies
Exactly how LRRK2 might influence progression in PSP remains to be seen. Come to think of it, researchers do not even fully understand how variants in the tau gene itself confer risk. In her talk, Alison Goate, Icahn School of Medicine at Mount Sinai, New York, reviewed the complexity of the MAPT locus at chromosome 17.

Goate showed how an inversion of a large DNA fragment at 17q21.31, which spans MAPT and multiple other genes, gives rise to the two major haplotypes H1 and H2 (Baker et al., 1999; Stefansson et al., 2005). People who carry H1 are at higher risk for both PD and PSP even though each disease has distinct clinical symptoms and neuropathology. How can this be? Kathryn Bowles, a postdoc in Goate’s lab, found that different sub-haplotypes hold the answer.

Researchers know that a sub-haplotype called H1c associates with PSP but not with PD. However, no one has mapped the association beyond the single nucleotide polymorphisms that tags H1c (Pittman et al., 2005; Hoglinger et al., 2011). In D.C., Goate showed that broader structural differences complicate this association. Namely, people with PSP have a different linkage disequilibrium pattern near the MAPT locus than do people with PD. In other words, PSP families inherit a structurally different version of this region of chromosome 17. “This suggests altered recombination or gene conversion in the MAPT 1 regulatory region,” said Goate. Gene conversion is where one copy of a DNA sequence is replaced by a homologous sequence.

How would such a structural difference manifest in disease risk? Because Bowles found no evidence that MAPT intron 1 variants associate with altered expression of tau, or of any other gene in the 17q21.31 locus, she wondered if the variants cause more dramatic changes, namely, in the way DNA is packaged. She used a technique called Assay for Transposase-Accessible Chromatin (ATAC-Seq), to test whether the chromatin near this locus is open and active, or closed. Bowles tested this in neurons induced from iPSC cells that were derived from people with the H1c haplotype. In these neurons, chromatin was open near SNPs that associate with PSP. The same was true in induced microglia, but not astrocytes.

In contrast, researchers know of no linkage disequilibrium shenanigans associated with Parkinson’s. That said, three H1 sub-haplotypes Bowles designated H1.1, H1.2, and H1.3, associated with PD in two independent case-control datasets. They correlated with expression of the astrocyte gene LRRC37A, but here the story gets even more complicated. Each of these sub-haplotypes can be further divided based on co-inherited SNPs, and some of those smaller haplotypes turned out to be the risk or protective variants. For example, H1.1b and H1.1e increased risk of PD, whereas H1.1c was protective.

All told, the genetic data suggest that the 17q locus has different kinds of association with PSP than with PD. In the former, altered chromatin in neurons and microglia increase risk in some way yet to be determined. In the latter, sub-haplotypes seem to modulate expression of LRRC37A, which encodes a cell membrane protein of unknown function. Gene ontology and pathway analysis predict it may function in chemotaxis, cell migration, and/or fatty acid metabolism.

As for PSP, Bowles can’t say for sure whether the risk comes from neurons or glia, but she leans toward the latter. “I think the argument for there being a larger, or at least unique, effect in microglia is quite compelling,” she said. “In the human brain ATAC-seq data, there are peaks in this region only in the NeuN-negative cells, nothing in the NeuN-positive cells. That points more to glia than to neurons.”—Tom Fagan

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References

News Citations

1. International Symposium Puts PSP/CBD on the Map 8 Nov 2018

Paper Citations

1. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999 Apr;8(4):711-5. PubMed.
2. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K. A common inversion under selection in Europeans. Nat Genet. 2005 Feb;37(2):129-37. Epub 2005 Jan 16 PubMed.
3. Pittman AM, Myers AJ, Abou-Sleiman P, Fung HC, Kaleem M, Marlowe L, Duckworth J, Leung D, Williams D, Kilford L, Thomas N, Morris CM, Dickson D, Wood NW, Hardy J, Lees AJ, de Silva R. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet. 2005 Nov;42(11):837-46. Epub 2005 Mar 25 PubMed.
4. Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011 Jun 19;43(7):699-705. PubMed.

External Citations

1. BRAINEAC
2. bioRxiv
3. Phase 1 clinical trial

Further Reading

No Available Further Reading