Association of TMEM106B Gene Polymorphism With Age at Onset in Granulin Mutation Carriers and Plasma Granulin Protein Levels

Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Archives of neurology (Impact Factor: 7.42). 05/2011; 68(5):581-6. DOI: 10.1001/archneurol.2010.350
Source: PubMed


To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.
Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.
Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.
Age at onset and GRN plasma levels.
The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.

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    • "The human linkage of FTLD-TDP risk to TMEM106B allele suggests that T185S variation plays a role. While this genetic variation alters PGRN levels in serum (Cruchaga et al., 2011; Finch et al., 2011), the effect may be direct or indirect. Tissue culture studies reveal either small or no effect of TMEM106B variants on PGRN levels (Brady et al., 2013; Lang et al., 2012). "
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    ABSTRACT: Fronto-temporal lobar degeneration with TDP-43 (FTLD-TDP) is a fatal neurodegeneration. TMEM106B variants are linked to FTLD-TDP risk, and TMEM106B is lysosomal. Here, we focus on neuronal TMEM106B, and demonstrate co-localization and traffic with lysosomal LAMP-1. pH-sensitive reporters demonstrate that the TMEM106B C-terminus is lumenal. The TMEM106B N-terminus interacts with endosomal adaptors and other TMEM106 proteins. TMEM106B knockdown reduces neuronal lysosomal number and diameter by STED microscopy, and overexpression enlarges LAMP-positive structures. Reduction of TMEM106B increases axonally transported lysosomes, while TMEM106B elevation inhibits transport and yields large lysosomes in the soma. TMEM106B overexpression alters lysosomal stress signaling, causing a translocation of the mTOR-sensitive transcription factor, TFEB, to neuronal nuclei. TMEM106B loss-of-function delays TFEB translocation after Torin-1-induced stress. Enlarged TMEM106B-overexpressing lysosomes maintain organelle integrity longer after lysosomal photodamage than do control lysosomes, while small TMEM106B-knockdown lysosomes are more sensitive to illumination. Thus, neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress, highlighting the possible role of lysosomal biology in FTLD-TDP.
    Molecular and Cellular Neuroscience 07/2014; 61. DOI:10.1016/j.mcn.2014.07.006 · 3.84 Impact Factor
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    • "Sortilin, serving as a cell-surface receptor for PGRN, regulates trafficking and targeting of PGRN to lysosomes [12]. The risk T allele on rs1990622 in the TMEM106B gene is linked to low plasma PGRN levels, suggesting that TMEM106B SNPs modulate secreted levels of PGRN [13,14]. A nonsynonymous SNP numbered rs3173615 (p.T185S) located in exon 6 of the TMEM106B gene shows complete linkage disequilibrium with rs1990622 [3,13,15]. "
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    ABSTRACT: TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer's disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown. By quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy and non-neurological cases. In AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN. We found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD.
    Alzheimer's Research and Therapy 03/2014; 6(2):17. DOI:10.1186/alzrt247 · 3.98 Impact Factor
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    • "Because FTLD is associated with loss-of-function mutations in GRN, one might predict that the protein this gene encodes (PGRN) would be diminished by the risk-associated allele of TMEM106B. Indeed, higher levels of PGRN are detected in the plasma of individuals carrying the protective S185 allele (or SNPs in linkage disequilibrium with that allele) (Cruchaga et al. 2011; Finch et al. 2011). However, Nicholson et al. (2013) report that overexpression of either the T or the S variant of TMEM106B leads to elevated steady-state levels of PGRN protein. "
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    ABSTRACT: Read the full article ‘TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia’ on doi:10.1111/jnc.12329.
    Journal of Neurochemistry 07/2013; 126(6). DOI:10.1111/jnc.12357 · 4.28 Impact Factor
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