13 Nov 2021

Researchers are debating whether primary age-related tauopathy (PART), the accumulation of tau tangles in the aging brain, is a natural part of aging, a forerunner to Alzheimer’s disease, or its own condition. In the November 1 Acta Neuropathologica, researchers led by John Crary at Icahn School of Medicine at Mount Sinai, New York, add evidence for the latter. They performed the first-ever GWAS for PART, genotyping samples from 647 postmortem brains. The only genome-wide significant hit was for a new risk gene, the adaptor protein JADE1. The scientists also turned up weak associations with three known AD genes and two genes linked to progressive supranuclear palsy, a pure tauopathy. The findings hint that PART shares genetic risk with both disorders.

PART was first defined by Crary and colleagues (Nov 2014 news). PART is nearly universal at advanced ages, and consists of tangle pathology up to Braak stage IV that is unaccompanied by any amyloid plaques. People with PART can be cognitively healthy, impaired, or have dementia. Because PART can only be diagnosed postmortem and lacks a clear clinical identity, it has been challenging to study.

To assemble a cohort large enough for a GWAS, first author Kurt Farrell requested tissue from 21 brain banks around the world. Of the 647 samples, 71 were Braak stage zero, 142 stage I, 189 stage II, 152 stage III, and 93 stage IV. Donors’ average age at death was 83, and two-thirds had been cognitively healthy at that time. Those who were impaired were spread evenly across Braak stages. Other work by the authors suggests that co-morbidities such as cerebrovascular disease account for cognitive decline in people with PART (Iida et al., 2021). 

The GWAS flagged a relatively common SNP near the JADE1 gene as a risk factor; having two copies of this minor allele associated with higher Braak stage. Because the SNP lay outside JADE1’s coding region, the authors searched for expression quantitative trait loci (eQTLs) that might affect gene expression. Using data from the ROSMAP cohort, they identified an eQTL for JADE1.

In the prefrontal cortices of PART brains, JADE1 expression was elevated in excitatory neurons that contained tangles, confirming a link between protein expression and pathology. The authors used phospho-tau antisera to sort tangle-bearing from tangle-free cells within a given brain sample, and then used single-soma RNA-Seq to compare gene expression between the two states.

Immunostaining for JADE1 localized the protein to neurofibrillary tangles. Alas, the scientists spotted JADE1 not only in tangles of PART brains, but also those of AD, PSP, corticobasal degeneration, and chronic traumatic encephalopathy. All these disorders accumulate either four-repeat tau or a mix of 3R/4R tau. JADE1 was not present in Pick’s disease deposits, which contain only 3R tau. Co-immunoprecipitation revealed that JADE1 binds to the 0N4R tau isoform, explaining this selectivity.

What does JADE1 do? To glean some clues, the authors knocked down its Drosophila ortholog, rhinoceros, in flies that overexpress human mutant 0N4R tau. This worsened the flies’ known eye neurodegeneration phenotype, suggesting that JADE1 might be neuroprotective. In wild-type flies, loss of JADE1 had no discernable effect. Because JADE1 is known to help ubiquitinate proteins, tagging them for degradation, it is possible it participates in clearing tau, the authors speculate.

In addition to JADE1, the authors examined 52 SNPs previously associated with AD or PSP for associations with PART. They found a link to the AD genes SLC24A4, MS4A6A, and HS3ST1, as well as the PSP genes MAPT and EIF2AK3. MS4A6A is involved in microglial activation, and HS3ST1 modifies heparan sulfate proteoglycans, which are believed to help spread misfolded tau. MAPT is the gene that makes tau, and EIF2AK3 an endoplasmic reticulum gene that monitors protein folding. All the candidate genes seem poised to affect tau pathology, the authors concluded.—Madolyn Bowman Rogers

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References

News Citations

1. Scientists Propose a New Definition for Tau-Only Pathology 7 Nov 2014

Paper Citations

1. Iida MA, Farrell K, Walker JM, Richardson TE, Marx GA, Bryce CH, Purohit D, Ayalon G, Beach TG, Bigio EH, Cortes EP, Gearing M, Haroutunian V, McMillan CT, Lee EB, Dickson DW, McKee AC, Stein TD, Trojanowski JQ, Woltjer RL, Kovacs GG, Kofler JK, Kaye J, White CL 3rd, Crary JF. Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study. Acta Neuropathol Commun. 2021 Aug 5;9(1):134. PubMed.

Further Reading

News

1. Flock of New Folds Fills in Tauopathy Family Tree 5 Oct 2021
2. Tau PET Aligns Spread of Pathology with Alzheimer’s Staging 11 Mar 2016