FTLD Gene Bad Actor in Many TDP-43 Proteinopathies

A variant of the TMEM106B gene, originally discovered in people with frontotemporal lobar degeneration with TDP-43 pathology, influences the TDP-43 protein in other neurodegenerative diseases too, according to a study in the February 4 Neurology online. Researchers at the Rush Alzheimer’s Disease Center in Chicago detected the variant in people with TDP-43 pathology but without FTLD, including those who were cognitively normal or had Alzheimer’s. Senior author Julie Schneider and colleagues also found that the polymorphism affected the expression of TMEM106B itself and of the FTLD gene progranulin, but the scientists still need to work out how those and other genes control TDP-43 pathology.

TDP-43 forms abnormal cytoplasmic inclusions in the brains of people with various neurodegenerative diseases, including amyotrophic lateral sclerosis, FTLD, as well as a fraction of cases of Alzheimer’s, Lewy body disease, and hippocampal sclerosis. TDP-43 was once viewed as a marker of damaged neurons; however, lately it has been shown to follow a standard pathway throughout the brain and correlate with clinical symptoms, write Keith Josephs of the Mayo Clinic in Rochester, Minnesota, and Peter Nelson of the University of Kentucky in Lexington, in an editorial accompanying the Neurology article (see Nov 2013 news; Jan 2014 news). “TDP-43 should join the inner circle of neurodegenerative misfolded proteins that now include β-amyloid, tau, and α-synuclein,” they propose.

What leads this newly appreciated pathological protein to aggregate? In 2010, a genome-wide association study offered up a hint: A stretch of DNA on chromosome seven, containing the gene TMEM106B, was associated with FTLD with TDP-43 pathology (see Feb 2010 news). Little was known about this gene, which encodes a transmembrane protein. Since then, researchers have determined that TMEM106B controls lysosome trafficking (see Aug 2012 news; Swenk et al., 2014; Stagi et al., 2014).

The original GWAS finding was based on an adenine/guanine polymorphism at a non-coding site near TMEM106B. The guanine indicated a 60 percent lower risk for FTLD. Researchers have not yet determined the sequence responsible for that protection, but they believe it must be a different variant that co-inherits with the guanine. In vitro studies suggest it might be a threonine-to-serine substitution at amino acid 185 of TMEM106B (Nicholson et al., 2013).

Going Beyond FTLD
Yu and colleagues wanted to understand how TMEM106B contributes to the spread of pathological TDP-43 across the brain in diseases other than FTLD. They analyzed autopsied brain tissue of 544 people, aged 71 or older at time of death, who did not meet pathological criteria for FTLD (see Cairns et al., 2007). As is typically the case with non-demented old people, the majority—82 percent—did have some sort of brain pathology, including plaques and tangles, Lewy bodies, hippocampal sclerosis, or a combination thereof. Before they died, about 70 percent of tissue donors across these pathologies had signs of cognitive impairment, Yu told Alzforum. Half of the brains had some level of TDP-43 pathology, and the higher-risk adenine allele associated with more advanced stages.

TMEM106B influences TDP-43 proteinopathy “above and beyond FTLD,” concluded Yu. Other researchers have also linked the TMEM106B to Alzheimer’s disease, hippocampal sclerosis, Lewy body disease, and amyotrophic lateral sclerosis (Rutherford et al., 2012; Nelson et al., 2015; Aoki et al., 2015; Vass et al., 2011).

Moreover, the correlation between TMEM106B status and TDP-43 spread held true regardless of any other neuropathology. “Even in normal people, TMEM106B genotype influences propensity to form TDP-43 pathology,” commented Alice Chen-Plotkin of the University of Pennsylvania School of Medicine, who was not involved in the study. She suggested those healthy individuals with the TMEM106B adenine allele and TDP-43 pathology may have taken one step on the road to FTLD or other neurodegenerative disease. Subsequent hits might be required to reach a symptomatic state, she speculated.

“It suggests that neurodegeneration could be a really long, slow process,” added Chen-Plotkin. As with the amyloid of Alzheimer’s and the α-synuclein of Parkinson’s, which take root well before thinking or movement are altered, TDP-43 seems to infiltrate the brain before a person shows signs of FTLD or other disease, she said.

TMEM106B and Gene Expression
Having shown that TMEM106B genotype affected TDP-43 proteinopathy, Yu and colleagues next analyzed how that might occur (see image below). TMEM106B has been shown to regulate its own expression as well as that of progranulin, another FTLD gene (see Nov 2010 news; Finch et al., 2011). Yu measured RNA amounts in the autopsy tissues, and confirmed that both TMEM106B and PGRN were upregulated in the people with the high-risk adenine TMEM106B allele.

Potential Pathways.

Several hypotheses for how TMEM106B genotype influences TDP-43 pathology. [Republished with permission, © 2015 American Academy of Neurology.]

Because other scientists have hypothesized that methylation suppresses progranulin expression, Yu and Schneider checked the status of 132 potential methylation sites in the progranulin locus (Banzhaf-Strathmann et al., 2013). Of these, five sites had slightly less methylation in people with the adenine TMEM106B locus, suggesting the variant might activate the PGRN gene.

“Their data and analysis provide key support for the hypothesis that TMEM106B variants are pathologically important and exert their influence upstream of expression of progranulin,” wrote Josephs and Nelson. Chen-Plotkin, who co-discovered the link between TMEM106B and FTLD, was pleased to see the effects on TMEM106B expression replicated in such a large cohort.

However, the results do not necessarily mean the TMEM106B genotype caused the progranulin overexpression, cautioned Rosa Rademakers and Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, who were not part of the study. TDP-43 proteinopathy itself causes neuroinflammation and microglial activation, and this would be sufficient to upregulate progranulin, they said (Ahmed et al., 2007). Yu and colleagues are testing for activated microglia in the autopsied tissue. Rademakers added that studying progranulin methylation with respect to TMEM106B genotype was a novel line of inquiry, but she thought the data were not conclusive. “It does not seem to be a strong effect,” she said.

The pathway between TMEM106B and TDP-43 is likely complex, said Carlos Cruchaga of the Washington University School of Medicine in St. Louis. “Here we are only seeing the first steps of the network,” he added. Yu also expects that many more genes participate in that cascade, and wants to use more genome-wide analyses of people with TDP-43 proteinopathy to identify those additional players.

References:

1. Yu L, De Jager PL, Yang J, Trojanowski JQ, Bennett DA, Schneider JA. The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology. 2015 Feb 4; PubMed.

2. Josephs KA, Nelson PT. Unlocking the mysteries of TDP-43. Neurology. 2015 Feb 4;PubMed.


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disease-ad disease-ftd tdp-43 topic-genetics topic-preclinical
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