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    • Tau helps assemble and stabilize microtubules In the

    2018-10-24

    Tau helps assemble and stabilize microtubules. In the CNS, several isoforms of tau are produced from a single gene by alternative splicing (Goedert et al., 1989). More than 40 pathogenic MAPT mutations have been described in more than 100 families with FTD (Cruts et al., 2012; Alzheimer Disease & Frontotemporal Dementia Mutation Database, http://www.molgen.vib-ua.be/FTDMutations). Many MAPT mutations are either missense mutations or small deletions in the coding region or in introns, which can affect alternative splicing (e.g., of exon 10) (Hutton et al., 1998; Niblock and Gallo, 2012). Tau also modulates signaling cascades by acting as scaffolding proteins for signaling complexes such as FYN, GRB2, and PLCγ, and may also affect other cellular functions (Ittner et al., 2010; Morris et al., 2011). Many studies of tau toxicity have used cellular or animal models in which wild-type (WT) or mutant tau is ectopically overexpressed (Morris et al., 2011; Wittmann et al., 2001). Patient-specific induced pluripotent stem protein kinase inhibitor (iPSCs) are an exciting alternative approach to study disease genes in their native genetic context (Yamanaka, 2007) and uncover novel pathogenic mechanisms in AD, Parkinson\'s disease, FTD, and other neurodegenerative disorders (Israel et al., 2012; Soldner et al., 2009; Almeida et al., 2012). Here we generated and characterized multiple iPSC lines from an FTD patient with a MAPT IVS10+16 mutation, an FTD patient with the tau-A152T variant, and a control subject. The MAPT IVS10+16 mutation is relatively common and found in many families in different countries (Hutton et al., 1998; Janssen et al., 2002). The tau-A152T variant has been shown to significantly increase the risk for both FTD and AD (Coppola et al., 2012; Kara et al., 2012) and induce aggregation-independent toxicity (Pir et al., 2016). To study their pathogenic mechanisms, we differentiated these newly generated iPSC lines, as well as published control and tau-A152T lines (Almeida et al., 2012; Fong et al., 2013) into postmitotic cortical neurons and identified upregulation of matrix metalloproteinase 9 (MMP-9) through the ERK pathway as an important pathogenic mechanism in FTD with MAPT mutations.
    Results
    Discussion In this study, we found a significant increase in the level and activity of secreted MMP-9 and MMP-2 in cortical neurons derived from iPSCs of three subjects with MAPT mutations. More importantly, this increase contributed to neuronal cell loss induced by cellular stress, and inhibition of MMP-9/MMP-2 activity was neuroprotective. Our results are consistent with a recent paper published during our study in which the authors showed that MMP-9 is specifically expressed in fast motor neurons and contributes to selective neuronal vulnerability in amyotrophic lateral sclerosis (ALS) (Kaplan et al., 2014). Moreover, reduction of MMP-9 through genetic or pharmacological approaches delayed muscle denervation in vivo (Kaplan et al., 2014). Thus, MMP-9 is a potential therapeutic target for both FTD and ALS, although how MMP-9 induces cell death in iPSC-derived cortical neurons remains to be determined at a mechanistic level. Our studies also provide mechanistic insight into the increased level and activity of secreted MMP-9 in cortical neurons derived from FTD patient-specific iPSCs with MAPT mutations. The increase seems to be mediated by ERK-pathway activation. Indeed, ectopic expression of mutant 4R but not 3R tau in HEK293 cells resulted in ERK phosphorylation and increased MMP-9 production. However, the molecular pathways of MMP-2 induction remain to be further delineated. These results further support the notion that tau is not only a key substrate for phosphorylation but also functions upstream of several kinase signaling pathways (Ittner et al., 2010; Morris et al., 2011; Vossel et al., 2015). Our iPSC lines with different MAPT mutations will be useful for further investigations of the roles of endogenous tau in cell signaling and neuronal vulnerability, such as in an accompanying paper by Silva et al. (2016). In the future, it will be useful to generate isogenic iPSC lines with different MAPT mutations and confirm the effect of endogenous mutant tau on the ERK-MMP-9 pathway. Moreover, since different tau strains with prion-like properties cause different tauopathies in vitro and in vivo (Sanders et al., 2014), it will be also interesting to determine which tau strains are present in iPSC-derived human neurons and activate the ERK pathway.