Previous studies indicated that polymorphisms in the TMEM106B gene exacerbate frontotemporal dementia caused by progranulin mutations, advancing disease onset by more than a decade. Now, new research strengthens the case for that synergy, and provides clues to how it works. In the December 16 JAMA Neurology, researchers led by Barbara Borroni at the University of Brescia, Italy, report that brain connections weakened by progranulin mutations are further compromised in patients who also carry the TMEM106B risk allele. By contrast, this allele did not affect connectivity in healthy controls. If the results need to be replicated in a larger group, they bolster the hypothesis that TMEM106B modulates disease severity and onset in people with progranulin mutations, Borroni told Alzforum.
Commentators agreed that these data complement genetic and molecular studies that showed a relationship between the genes. “This extends efforts to define the biology of the TMEM106B polymorphism. I think this paper will fuel interest in doing additional studies,” said John Trojanowski at the University of Pennsylvania, Philadelphia. Rosa Rademakers at the Mayo Clinic in Jacksonville, Florida, called the data exciting. “After the initial discovery of TMEM106B there had been some conflicting replication studies, but this new data, combined with recent functional data, further confirm the importance of this protein in FTD,” she wrote to Alzforum.
Progranulin mutations that disrupt protein function account for about 20 percent of familial and up to 10 percent of sporadic FTD (see Apr 2007 conference story; Rademakers et al., 2007). Scientists are still trying to find out exactly how a lack of progranulin leads to disease, although some researchers have pointed to the protein’s neurotrophic properties and role in curbing inflammation (see Mar 2011 news story; Oct 2012 news story). The story got more interesting when researchers identified polymorphisms that pump up expression of TMEM106B, a transmembrane protein found in lysosomes, more than doubling the risk for FTD (see Feb 2010 news story). Intriguingly, these polymorphisms associated with low levels of plasma progranulin (see Cruchaga et al., 2011; Finch et al., 2011). Recent work suggests that TMEM106B regulates trafficking of progranulin, with too much TMEM106B keeping progranulin levels high in the cell (see Aug 2012 news story). It is unclear how this relates to plasma progranulin.
Borroni and colleagues wanted to find out if TMEM106B also interacted with progranulin to modulate brain systems. In previous studies, the authors found that, in cognitively healthy adults who carry a progranulin mutation, brain connectivity was changed up to two decades before they would be expected to develop symptoms (see Borroni et al., 2012). In the current study, first author Enrico Premi performed resting-state functional magnetic resonance imaging (fMRI) on 17 progranulin carriers and 14 healthy controls. All participants were cognitively healthy, with an average age of 40. Consistent with the earlier work, in mutation carriers connectivity was weaker in the left frontoparietal network and stronger in the executive network compared with controls. Four people who also carried the TMEM106B risk polymorphism showed additional weakening in frontoparietal connections, as well as in the ventral salience network. These networks control the type of judgment and reasoning abilities that are most affected by FTD.
While the number of patients with TMEM106B risk alleles was small, the cross-sectional data hints that TMEM106B genotyping could help refine the prognosis for people with progranulin mutations, Borroni said. She will follow this cohort to investigate their trajectory of brain changes as symptoms appear, and also wants to replicate the findings in a larger group.
Exactly how these gene variants might change the brain’s connective pathways remains a mystery. Because progranulin promotes growth, its lack might lead to cellular damage and atrophy, Borroni speculated. Progranulin mutation carriers accumulate aggregates of the RNA-binding protein TDP-43 in the brain. These foci are pathological features of FTD and motor neuron disease. Trojanowski noted that a recent collaborative study with Heiko Braak's lab at the University of Ulm, Germany, hints that TDP-43 may spread across the brain (see Nov 2013 conference story; Brettschneider et al., 2013), similar to the way other pathogenic proteins are believed to propagate from cell to cell along neuronal pathways (see Aug 2013 conference story). If so, the transmission of TDP-43 might be disrupting connections downstream from TMEM106B and progranulin mutations, he suggested.
Erosion of brain connections may be a general feature of neurodegenerative disease. In Alzheimer’s as well, connectivity weakens in brain networks years before symptoms, and correlates with other early biomarkers (see Jul 2012 news story; Jul 2013 news story; Aug 2013 news story). Functional MRI is far from being ready to be used broadly as a validated biomarker, but because of its sensitivity to early changes, it is increasingly being explored in longitudinal studies and some clinical trials.—Madolyn Bowman Rogers
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- Microglial Progranulin Douses Neural Inflammation
- Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS
- The Four Stages of TDP-43 Proteinopathy
- Communication Breakdown: Multiple Networks Decline in AD Brains
- Atrophy of Distinct Brain Networks May Explain Alzheimer’s Variants
- Brain Connectivity Reveals Preclinical Alzheimer’s Disease
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