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Monday
Mar202017

65 is the new 77, in some; TMEM106B gene variants accelerate normal brain aging

Understanding factors linked to normal development and aging of the brain is an essential step in defining molecular features of brain disease. Age-related research is challenging – vast differences are apparent on an individual level with respect to chronological age and cognition (to take only a single example!). Even in the aging people I know (sorry, parents, it’s true!) it’s obvious that even in good health, age impacts each brain differently.  

 A new report from Columbia University Medical Center in the journal Cell Systems has used gene expression and genome-wide association (GWAS) methods to refine genetic details of normal age-associated phenotypes via ‘differential aging’. Using postmortem samples from cerebral cortex, authors Rhinn and Abeliovich first investigated the transcriptome profiles from nearly 2000 individuals. They used these data to identify an age-dependent set of genes and then based on the correlation of gene expression with known age, estimated the aging rate of each individual sample. Amazingly, in samples from individuals >65 years old, the aging rate in the cerebral cortex was found to be accelerated by as many as 12 years.

 Some samples suggested that aging was progressing faster than in others. To further understand this, the authors then used GWAS analysis to investigate the relationship of genetic polymorphisms (like typographical errors in the sequences of genes) throughout the genome to rate of aging.  Two surprising results came back:

In a Manhattan plot, the tallest ‘skyscrapers’ evident in plots of the GWAS data suggested that a highly significant impact on ageing rate was linked to polymorphisms in the gene TMEM106B and, to a lesser extent, GRN (the gene encoding the granulin protein). 

 TMEM106B encodes the transmembrane protein 106B, involved in the maintenance of dendrites – essential branch-like projections from neural cells that enable communication between cells in the brain.  Work in the last 5-10 years has already implicated TMEM106B and GRN in age-related neurodegenerative diseases including Frontotemporal dementia and Alzheimer’s disease (see further reading). However, the new results from Rhinn and Abeliovich demonstrate that genetic issues with TMEM106B and GRN contribute to age-related decline in cognition, elevated neuroinflammation and neuronal loss, even in the absence of known brain disease.

 Our lab’s ongoing work is actively visualizing new targets that may be related to brain aging. Overlaying information about TMEM106B and GRN polymorphisms could enrich our understanding about comprehensive factors that influence the way the healthy brain ages – and better map the molecular profiles of unhealthy brain aging via brain disease.

 ~FAS

 Article: Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes. Rinn H & Abeliovich A. Cell Systems, Online March 16, 2017,

DOI: http://dx.doi.org/10.1016/j.cels.2017.02.009

 

Further Reading:

1. What we know about TMEM106B in Neurodegeneration. Nicholson AM & Rademakers R. Acta Neuropathol. 2016 Nov; 132(5):639-651. 

2. Reassessment of Risk Genotypes (GRN, TMEM106B, and ABCC9 Variants) Associated with Hippocampal Sclerosis of Aging Pathology. Nelson PT, et al. J.Neuropathol.Exp.Neurol. 2015 Jan;74(1):75-84.

3. TMEM106B, the Risk Gene for Frontotemporal Dementia, is Regulated by the microRNA-132/212 Cluster and Affects Progranulin Pathways. Chen-Plotkin AS, et al. J.Neurosci. 2012 Aug 15; 32(33):11213-27.

4. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Finch N, et al. Neurology. 2011 Feb 1; 76(5):467-74. 

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