Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, Wang C, Huang C, Sohn PD, Bowles KR, Spina S, Silva MC, Marsh JA, Hsu S, Pugh DA, Ghoshal N, Norton J, Huang Y, Lee SE, Seeley WW, Theofilas P, Grinberg LT, Moreno F, McIlroy K, Boeve BF, Cairns NJ, Crary JF, Haggarty SJ, Ichida JK, Kosik KS, Miller BL, Gan L, Goate AM, Temple S, Tau Consortium Stem Cell Group. A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies. Stem Cell Reports. 2019 Nov 12;13(5):939-955. Epub 2019 Oct 17 PubMed.

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Comments

  1. In this paper, we are witness to a momentous birth announcement, presenting the work of a talented, multidisciplinary group of scientists focused on tauopathies. Over at least the past two decades, the tau protein and Tau gene have been studied first as phenotypic markers and increasingly as both genetic and prion-like drivers of neurodegenerative diseases, including some types of FTLD, PSP, CBD, and AD. Terrific insights have come from forced overexpression models employing mutant Tau (PS19 mice, for instance) in vivo and in vitro, where toxicity of abnormal tau protein species (mutant or misfolded WT) have been characterized. Even so, the relevance of these model systems to critical drivers of pathogenesis in patients, and their utility as the generator of phenotypes to be modified in drug screens, remains uncertain. We’re just beginning to read out the first therapeutic candidates that were screened using these legacy models as part of their preclinical proof-of-concept packages.

    This paper describes the initial set of fibroblasts, iPS cells, and neural progenitor cells derived from FTLD/PSP/CBD patients now available to both basic scientists and drug developers who wish to target Tau-mediated disorders. The resource includes a number of distinct, known pathogenic Tau mutations derived from well-characterized patients/families. Importantly, the resource includes several isogenic lines that differ only in regard to the presence or absence of a particular, pathogenic tau mutation—effectively allowing researchers to control for differences in genetic background or modifier genes that might otherwise cloud interpretation of experimental results.

    Two other critical points are worth emphasizing. First, some lines were derived from patients without Tau mutations. Because most cases of PSP and CBD are “sporadic” and do not harbor Tau mutations, study of these lines may provide additional information on modifier genes that affect tau production or elimination. Second, the consortium that developed this resource continue to generate additional lines for study of Tau-mediated disorders.

    Patients, families, researchers, and companies are enthusiastic about accessing these new lines and appreciate the open access provided by the researchers and funding organizations that have supported this initiative.

    View all comments by Jeff Friedman

  2. The importance of iPSC resource for primary tauopathies

    Tauopathies are a group of neurodegenerative diseases representing pathological inclusions composed of aggregates and modified forms of microtubule-associated protein Tau (MAPT). Tau inclusions can co-exist with other pathological protein aggregates such as Aβ in Alzheimer’s disease. However, Tau aggregates can also be the primary factor driving neurodegeneration in diseases classified as primary tauopathies. The latter can be sporadic or associated with mutations in the MAPT gene predisposing for Tau pathology. Tau pathology is explained via two main mechanisms. First, aggregates of Tau protein may disrupt the cellular process to cause neuronal degeneration (gain of toxic function theory). Secondly, Tau post-translational modifications (e.g. phosphorylation) may interfere with the physiological function of Tau as a microtubule-binding protein, leading to microtubule destabilization and consequently impairment of axonal transport (loss-of-function theory).

    Despite all knowledge obtained on Tau-dependent neurodegeneration in the past decades, there is still no approved therapy for tauopathies. Many aspects of Tau pathology are still unknown, such as the trigger factors for pathology, the differential sensitivity of cells toward tau pathology, and the cellular and molecular mechanisms of Tau propagation. Studying the biological consequences of Tau mutations in models of primary tauopathies provides a unique opportunity to decipher disease mechanisms and to develop Tau-targeting therapies.

    A big challenge remains to create a model system that is as close as possible to the human disease. Patient-derived cell models are still in the process of optimization, but a major step forward has been achieved by Karch and colleagues by establishing a comprehensive resource for induced pluripotent stem cell (iPSC) lines from patients with primary tauopathies.

    This resource of iPSC lines is therefore an enormously valuable asset in the research on Tau-related neurodegenerative diseases. Having a pool of cell lines with different disease-linked mutations and risk variants from several individuals and their isogenic control cells is an excellent resource for the research community to enlighten disease mechanisms. Different mutations in the MAPT gene have different effects on the Tau protein. While some mutations have been associated with a changed 3R/4R Tau ratio (Liu and Gong, 2008), others are known to alter the protein sequence (Fischer et al., 2007). Therefore, the variety of available cell lines and their mutations will help to model the different aspects of relevant disease mechanisms. In addition, having detailed clinical data for most of the individuals from whom the cell lines were generated is a major advance.

    The current limitation of iPSC models is their relative immaturity in terms of neuronal differentiation. Without an extensive culturing period, only the fetal Tau isoform is expressed in iPSC-derived neurons (Sposito et al., 2015). Since quite a number of mutations in the MAPT gene effect the 4R Tau isoform splicing, this issue is of crucial relevance. Improvements in differentiation protocols are needed to speed up the maturation process and induce a switch to a Tau isoform profile more closely resembling the adult brain. Recent findings (Miguel et al., 2019) show that three-dimensional culturing of neurons can reduce the differentiation time until all six Tau isoforms are expressed in iPSC and allow us to be optimistic that current challenges of this model system can be overcome in the future.

    References:

    Fischer D, Mukrasch MD, von Bergen M, Klos-Witkowska A, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M. Structural and microtubule binding properties of tau mutants of frontotemporal dementias. Biochemistry. 2007 Mar 13;46(10):2574-82. PubMed.

    Liu F, Gong CX. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener. 2008 Jul 10;3:8. PubMed.

    Miguel L, Rovelet-Lecrux A, Feyeux M, Frebourg T, Nassoy P, Campion D, Lecourtois M. Detection of all adult Tau isoforms in a 3D culture model of iPSC-derived neurons. Stem Cell Res. 2019 Oct;40:101541. Epub 2019 Aug 23 PubMed.

    Sposito T, Preza E, Mahoney CJ, Setó-Salvia N, Ryan NS, Morris HR, Arber C, Devine MJ, Houlden H, Warner TT, Bushell TJ, Zagnoni M, Kunath T, Livesey FJ, Fox NC, Rossor MN, Hardy J, Wray S. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet. 2015 Sep 15;24(18):5260-9. Epub 2015 Jul 1 PubMed.

    View all comments by Günter Höglinger

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This paper appears in the following:

News

  1. Introducing: iPSC Collection from Tauopathy Patients

Mutations

  1. MAPT R5H
  2. MAPT P301S
  3. MAPT P301L