Researchers have added amyotrophic lateral sclerosis (ALS) to the list of neurodegenerative diseases for which the immunomodulatory gene TREM2 is a risk factor. Writing in the February 17 JAMA Neurology, researchers led by Matthew Harms at Washington University in St. Louis, report that people harboring a copy of the TREM2 variant R47H face more than double the odds of developing ALS.
“This finding is very provocative and compelling, and it will be exciting to see if it can be confirmed in other studies,” Robert Brown at the University of Massachusetts Medical School in Worcester, who was not involved in the study, told Alzforum. The findings may underscore the important role of microglia—the resident brain macrophages known to express TREM2—in staving off neurodegeneration, he said.
Researchers created a stir in 2012 when they reported that people who carry one copy of the R47H mutation have triple the chances of developing Alzheimer’s disease, putting TREM2 on par with the strongest genetic risk factor for sporadic AD, ApoE4 (see Guerreiro et al., 2013; Jonsson et al., 2013). TREM2 had previously been linked to frontotemporal dementia, and last year scientists identified the variant as a risk factor for Parkinson’s as well (see Ruiz et al., 2013; Wunderlich et al., 2013 and Rayaprolu et al., 2013). Those genetic studies found no ties to ALS. However, clinicopathological research has implicated chronically activated microglia—which express TREM2—in the disease (see Brettschneider et al., 2012).
Given this clue, first author Janet Cady and colleagues searched for a link between the TREM2 R47H variant and ALS. From a cohort of white, non-Hispanics who get care at ALS clinics in the United States, they genotyped 1,848 controls and 920 people with the disease. Patients were about seven times likelier to harbor the TREM2 variant. However, when the researchers included 25,023 controls from several European cohorts, plus ALS and control samples from a smaller previous study that failed to find a correlation, and analyzed that larger dataset, the risk dropped to 2.4-fold—commensurate with the risk increase seen for AD.
How might this variant cause disease? The researchers sought to determine if TREM2 expression changes in ALS. Because the R47H mutation is rare, they looked at TREM2 levels in patients with normal copies of the gene. Cady found TREM2 expression was elevated nearly threefold in postmortem spinal cord samples from 18 patients. Transgenic mice expressing the SOD1-G93A mutation, a cause of familial ALS, had 13 times more TREM2 RNA in the spinal cord than did their non-transgenic littermates. Taken together, the findings suggest that TREM2 expression, or the number of cells that express TREM2, increases in the spinal cords of people with ALS. It remains to be determined whether the R47H variant alters this expression.
It is also unclear if the mutation affects the function of TREM2, or even which type of cell is involved in mediating ALS damage caused by the variant, Harms said. Arginine 47 sits in the protein’s extracellular domain and may affect ligand binding, but TREM2 ligands have yet to be discovered. Microglia are likely central players, Harms said, though these cells use TREM2 in many diverse functions, including gobbling up dead and dying cells, fighting infection, and dousing potentially damaging inflammatory responses. The mutation might affect any or all of these processes.
Identifying TREM2’s role in ALS could help researchers understand pathology in neurodegenerative diseases more broadly. “Mutations in TREM2 predispose people to dysregulated microglia responses,” said Monica Carson at the University of California, Riverside. “Having this [microglial] imbalance by itself does not cause disease, but it can increase your risk.”
Harms agreed. “It may be that while other environmental or genetic exposures determine which type of disease someone may get, the TREM2 mutation tips them over the edge,” he said. For example, mutations in APP cause only AD, not ALS, FTD, or PD. Harms plans to determine what role this TREM2 variant plays in the severity and progression of ALS.
Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, Baloh RH, Ravits J, Simpson E, Appel SH, Pestronk A, Goate AM, Miller TM, Cruchaga C, Harms MB. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014 Apr;71(4):449-53. PubMed.
Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Josephs KA, Knopman DS, White CL, Caselli R, Mackenzie IR, Miller BL, Boczarska-Jedynak M, Opala G, Krygowska-Wajs A, Barcikowska M, Younkin SG, Petersen RC, Ertekin-Taner N, Uitti RJ, Meschia JF, Boylan KB, Boeve BF, Graff-Radford NR, Wszolek ZK, Dickson DW, Rademakers R, Ross OA. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease. Mol Neurodegener. 2013;8:19. PubMed.
Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One. 2012;7(6):e39216. PubMed.
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