Many genetic variants that lead to neurodegenerative disease are rare, and so scientists cannot obtain enough brain tissue for mechanistic studies. Researchers led by Celeste Karch, Carlos Cruchaga, and Oscar Harari at Washington University School of Medicine, St. Louis, came up with an alternate approach. They combined gene-expression analysis in human neurons derived from iPSCs with validation in postmortem tissue and, for good measure, probed GWAS datasets. In the December 13 Translational Psychiatry, they describe how this three-way marriage turned up a relationship between the R406W tau mutation and loss of GABAergic signaling.
- Neurons expressing the R406W tau mutation lose GABA receptors.
- The same thing occurs in sporadic FTD and PSP.
- Impaired GABAergic signaling may be a general feature of tauopathies.
R406W causes a specific form of frontotemporal dementia, but the researchers believe the finding may hold across tauopathies. They found similar GABAergic dysfunction in postmortem tissue from people with sporadic FTD or progressive supranuclear palsy, but not in Alzheimer’s disease. “There is a lot we still need to learn about the biology of these diseases. This approach can be applied to other mutations to help us understand how genetic variants lead to disease,” Cruchaga told Alzforum.
Kenneth Kosik at the University of California, Santa Barbara, found the differences between FTD and AD tissue provocative, saying, “If there’s some selective vulnerability of GABAergic neurons to tauopathy, that would be an interesting and potentially novel insight. This is a great first step.”
Tauopathy Network. Gene-expression analysis of a type of frontotemporal dementia identified 61 genes whose expression was altered. They form an interaction web centered around GABAergic signaling. [Courtesy of Jiang et al., Translational Psychiatry.]
Tau pathology is common in several neurodegenerative diseases, including Alzheimer’s. However, pathogenic variants in the tau gene, MAPT, do not lead to AD but to frontotemporal dementia. People who carry one copy of R406W usually develop memory problems in their 50s. Their disease progresses slowly and is often mistaken for AD. Later, carriers develop more typical FTD symptoms, such as personality changes and disinhibition, and sometimes have problems walking. At autopsy, their brains harbor tau tangles similar to those seen in AD. Homozygous carriers succumb up to two decades earlier, starting out with agitation. Exactly how R406W causes disease is not known.
To explore this, first author Shan Jiang compared neurons made from a single donor with the R406W mutation to isogenic control neurons whose R406W tau was corrected with CRISPR. In other words, they were able to compare neurons with the exact genome of the patient to neurons that were identical but for the disease-causing mutation. Transcriptome analysis identified 328 genes that were differently expressed between the two cell lines. Were these expression changes associated with pathology? To find out, the scientists analyzed the RNA profiles of postmortem tissue from the insular and parietal cortices of two people with R406W and two healthy controls. Sixty-one of the 328 genes replicated in these samples, changing in the same direction and to the same degree in diseased human tissue as they had in cultured R406W neurons.
What did these 61 do? Functional analysis placed many of them into GABAergic signaling and presynaptic function. Two of the genes, synaptosome-associated protein 25 (SNAP25) and synaptotagmin 1 (SYT1), help vesicles to dock and release neurotransmitters. SNAP25 and SYT1 were hub genes that were functionally connected to many of the others in the set of 61 (see image above). Two more, GABRB2 and GABRG2, encode GABA receptor subunits. Levels of GABRB2 and GABRG2 were low in cultured neurons and brain tissue from R406W carriers, implying less inhibitory GABAergic signaling. Supporting this, the researchers measured additional receptors and found a general downregulation of GABA receptors, but not other neurotransmitter receptors, in neurons and brain tissue from carriers.
It’s not just R406W FTD. The authors found suppression of GABA receptors in multiple tauopathies. Mice expressing the tauopathy mutation P301L lost GABA receptors starting at 18 months of age, when neurodegeneration begins in this model. GABA receptors were down in postmortem temporal cortex and cerebellum samples from 84 people with PSP, compared with 80 healthy controls. Finally, GWAS data from the International FTD Genomics Consortium contained numerous risk variants associated with sporadic FTD in the vicinity of the 61 genes, the scientists reported.
The GABAergic findings seem to be specific to tauopathies, however. The authors examined gene expression in postmortem parietal cortex samples from 80 people with late-onset AD, 18 with autosomal-dominant AD, 11 people with FTLD characterized by TDP-43 deposits, and 11 healthy controls. They saw no changes in expression of any of the 328 genes between these samples.
“Based on our findings, we think GABA receptors are linked to tau pathology when tau is the main driver of disease,” Cruchaga said.
Previous research has implicated the GABAergic system in tauopathies. P301L mice lose GABAergic neurons, as do A152T roundworm models and A152T neurons in culture (Levenga et al., 2013; Fong et al., 2013; Pir et al., 2016). Researchers have also found interneuron loss in PSP brain (Levy et al., 1995; Ferrer, 1999).
Could researchers boost GABAergic signaling to ameliorate symptoms of tauopathy? Cruchaga believes this approach is worth exploring. The WashU group identified 32 existing drugs that target GABRB2 or GABRG2. Cruchaga will test these in the iPSC-derived neuronal cultures to see if they restore normal gene expression. “We’re excited by the potential to repurpose these drugs for tauopathies,” he told Alzforum.
Might suppression of GABA signaling have anything to do with the social disinhibition that plagues many FTD patients and their caregivers? Kosik thinks this unlikely. “GABA-mediated inhibition occurs at a cellular level, and most CNS neural transmission is modulated by both glutamatergic and GABAergic inputs. On the other hand, social inhibition operates at the level of entire brain regions like the prefrontal cortex,” he wrote to Alzforum. Cruchaga agreed, noting that R406W carriers tend to maintain appropriate social behavior until late in their disease course.
What about Alzheimer’s disease? Some studies have shown excess neuronal activity in AD, suggesting a loss of inhibitory signaling (Sep 2008 news; Nov 2009 conference news). However, the picture is fuzzy. While ApoE knock-in mice lose GABAergic neurons with age, these cells are relatively preserved in AD (Nov 2002 conference news; Feb 2012 conference news). Other studies suggest the problem in AD could be too much GABA signaling, perhaps as a compensatory response to hyperactive neurons (Mar 2007 news; Sep 2007 news; Jul 2014 news).—Madolyn Bowman Rogers
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- Ferrer I. Neurons and their dendrites in frontotemporal dementia. Dement Geriatr Cogn Disord. 1999;10 Suppl 1:55-60. PubMed.
- Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, Martinez R, Hsu S, Fernandez MV, Cairns NJ, Dominantly Inherited Alzheimer Network (DIAN), International FTD-Genomics Consortium (IFGC), Harari O, Cruchaga C, Karch CM. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Transl Psychiatry. 2018 Dec 13;8(1):265. PubMed.