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Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

M Catarina Silva, Fleur M Ferguson, Quan Cai and 11 more

eLife · 2019 · CC BY

doi:10.7554/elife.45457

Abstract

Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas. Positron emission tomography (PET) tracers that bind to pathological tau are used in diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET-probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01–175 was designed to engage both tau and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, to trigger tau ubiquitination and proteasomal degradation. QC-01–175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, with minimal effect on tau from neurons of healthy controls, indicating specificity for disease-relevant forms. QC-01–175 also rescued stress vulnerability in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.

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    Not in our library10.1016/j.stemcr.2016.08.001

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    Silva MC, Cross A, Brandon NJ, Haggarty SJ, Rotella D. avidP, Ward S. imonE, Chackalamannil S. amuel. Comprehensive Medicinal Chemistry III. 2017;48-73.

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    Smith R, Puschmann A, Schöll M, Ohlsson T, van Swieten J, Honer M, Englund E, Hansson O. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. Brain. 2016;139:2372-2379.

    Not in our library10.1093/brain/aww163

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    Smith R, Wibom M, Pawlik D, Englund E, Hansson O. Correlation of In Vivo [18F]Flortaucipir With Postmortem Alzheimer Disease Tau Pathology. JAMA neurology. 2018.

    Not in our library10.1001/jamaneurol.2018.3692

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    Spina S, Schonhaut DR, Boeve BF, Seeley WW, Ossenkoppele R, O'Neil JP, Lazaris A, Rosen HJ, Boxer AL, Perry DC, Miller BL, Dickson DW, Parisi JE, Jagust WJ, Murray ME, Rabinovici GD. Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations. Neurology. 2017;88:758-766.

    Not in our library10.1212/wnl.0000000000003636

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    Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. The American Journal of Pathology. 2006;168:1598-1607.

    Not in our library10.2353/ajpath.2006.050840

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    Tian H, Davidowitz E, Lopez P, Emadi S, Moe J, Sierks M. Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. International Journal of Cell Biology. 2013;2013:1-9.

    Not in our library10.1155/2013/260787

  90. 90.

    Vermeiren C, Motte P, Viot D, Mairet-Coello G, Courade JP, Citron M, Mercier J, Hannestad J, Gillard M. The tau positron-emission tomography tracer AV-1451 binds with similar affinities to tau fibrils and monoamine oxidases. Movement Disorders. 2018;33:273-281.

    Not in our library10.1002/mds.27271

  91. 91.

    Wan W, Cao L, Kalionis B, Xia S, Tai X. Applications of induced pluripotent stem cells in studying the neurodegenerative diseases. Stem Cells International. 2015;2015:1-11.

    Not in our library10.1155/2015/382530

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    Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Human Molecular Genetics. 2009;18:4153-4170.

    Not in our library10.1093/hmg/ddp367

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    Wang Y, Mandelkow E. Degradation of tau protein by autophagy and proteasomal pathways. Biochemical Society Transactions. 2012;40:644-652.

    Not in our library10.1042/bst20120071

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    Xia CF, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C, Mocharla VP, Mu F, Sinha A, Su H, Szardenings AK, Walsh JC, Wang E, Yu C, Zhang W, Zhao T, Kolb HC. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Alzheimer's & Dementia. 2013;9:666-676.

    Not in our library10.1016/j.jalz.2012.11.008

  95. 95.

    Xie T, Lim SM, Westover KD, Dodge ME, Ercan D, Ficarro SB, Udayakumar D, Gurbani D, Tae HS, Riddle SM, Sim T, Marto JA, Jänne PA, Crews CM, Gray NS. Pharmacological targeting of the pseudokinase Her3. Nature Chemical Biology. 2014;10:1006-1012.

    Not in our library10.1038/nchembio.1658

  96. 96.

    Xu H, Rösler TW, Carlsson T, de Andrade A, Fiala O, Hollerhage M, Oertel WH, Goedert M, Aigner A, Höglinger GU. Tau silencing by siRNA in the P301S mouse model of tauopathy. Current Gene Therapy. 2014;14:343-351.

    Not in our library10.2174/156652321405140926160602

  97. 97.

    Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402-414.

    Not in our library10.1016/j.neuron.2013.07.046

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