TMEM106B, the Risk Gene for Frontotemporal Dementia, Is Regulated by the microRNA-132/212 Cluster and Affects Progranulin Pathways

Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2012; 32(33):11213-27. DOI: 10.1523/JNEUROSCI.0521-12.2012
Source: PubMed


Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurodegenerative disease with no available treatments. Mutations in the progranulin gene (GRN) causing impaired production or secretion of progranulin are a common Mendelian cause of FTLD-TDP; additionally, common variants at chromosome 7p21 in the uncharacterized gene TMEM106B were recently linked by genome-wide association to FTLD-TDP with and without GRN mutations. Here we show that TMEM106B is neuronally expressed in postmortem human brain tissue, and that expression levels are increased in FTLD-TDP brain. Furthermore, using an unbiased, microarray-based screen of >800 microRNAs (miRs), we identify microRNA-132 as the top microRNA differentiating FTLD-TDP and control brains, with <50% normal expression levels of three members of the microRNA-132 cluster (microRNA-132, microRNA-132*, and microRNA-212) in disease. Computational analyses, corroborated empirically, demonstrate that the top mRNA target of both microRNA-132 and microRNA-212 is TMEM106B; both microRNAs repress TMEM106B expression through shared microRNA-132/212 binding sites in the TMEM106B 3'UTR. Increasing TMEM106B expression to model disease results in enlargement and poor acidification of endo-lysosomes, as well as impairment of mannose-6-phosphate-receptor trafficking. Finally, endogenous neuronal TMEM106B colocalizes with progranulin in late endo-lysosomes, and TMEM106B overexpression increases intracellular levels of progranulin. Thus, TMEM106B is an FTLD-TDP risk gene, with microRNA-132/212 depression as an event which can lead to aberrant overexpression of TMEM106B, which in turn alters progranulin pathways. Evidence for this pathogenic cascade includes the striking convergence of two independent, genomic-scale screens on a microRNA:mRNA regulatory pair. Our findings open novel directions for elucidating miR-based therapies in FTLD-TDP.

  • Source
    • "Loss of lysosomal PGRN signal is accompanied by increased secretion of PGRN to the extracellular space (Fig. 3, C and D) and increased colocalization of PGRN with the ER marker PDI (Fig. 3 E). To rule out a general defect of lysosomal targeting in PSAP −/− fibroblasts, we examined the localization of two other lysosomal proteins, cathepsin D and TMEM106B (Chen-Plotkin et al., 2012;Lang et al., 2012;Brady et al., 2013). Both cathepsin D and TMEM106B are lysosomally localized in PSAP −/− fibroblast (Fig. 4, A and B), confirming that PSAP deficiency does not cause a general defect in lysosomal trafficking . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1. PSAP deficiency in mice leads to severe PGRN trafficking defects and a drastic increase in serum PGRN levels. We further showed that this PSAP pathway is independent of, but complementary to, the previously identified PGRN lysosomal trafficking mediated by sortilin. Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.
    Full-text · Article · Sep 2015 · The Journal of Cell Biology
  • Source
    • "While these studies point to the potential importance of these miRNAs in cognition, direct evidence implicating endogenous miR-132 and miR-212 in vivo is still lacking. Interestingly, miR-132 and miR-212 are amongst the most robustly downregulated miRNAs in neurodegenerative disorders, including Alzheimer's disease (AD) [22] [23] [24] [25], Huntington's disease (HD) [26] [27], Parkinson's disease (PD) [28], and frontotemporal dementia [22] [29]. The clinical significance of these observations remains however uncertain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6 month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wildtype controls in general locomotor activity in an open-field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · Behavioural brain research
  • Source
    • "The localization of TMEM106B to the endo-lysosomal pathway is highly specific. Previous studies have reported this localization in several cell lines and neurons (Brady et al., 2013; Chen-Plotkin et al., 2012; Lang et al., 2012). Our time-lapse analysis of LAMP1 and TMEM106B co-traffic in neuronal organelles provides a dramatic confirmation of this point. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jul 2014 · Molecular and Cellular Neuroscience
Show more