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Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis

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Abstract

Heterozygous loss-of-function mutations in the progranulin (GRN) gene and the resulting reduction of GRN levels is a common genetic cause for frontotemporal lobar degeneration (FTLD) with accumulation of TAR DNA-binding protein (TDP)-43. Recently, it has been shown that a complete GRN deficiency due to a homozygous GRN loss-of-function mutation causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. These findings suggest that lysosomal dysfunction may also contribute to some extent to FTLD. Indeed, Grn(−/−) mice recapitulate not only pathobiochemical features of GRN-associated FTLD-TDP (FTLD-TDP/GRN), but also those which are characteristic for NCL and lysosomal impairment. In Grn(−/−) mice the lysosomal proteins cathepsin D (CTSD), LAMP (lysosomal-associated membrane protein) 1 and the NCL storage components saposin D and subunit c of mitochondrial ATP synthase (SCMAS) were all found to be elevated. Moreover, these mice display increased levels of transmembrane protein (TMEM) 106B, a lysosomal protein known as a risk factor for FTLD-TDP pathology. In line with a potential pathological overlap of FTLD and NCL, Ctsd(−/−) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B. In addition, pathologically phosphorylated TDP-43 occurs in Ctsd(−/−) mice to a similar extent as in Grn(−/−) mice. Consistent with these findings, some NCL patients accumulate pathologically phosphorylated TDP-43 within their brains. Based on these observations, we searched for pathological marker proteins, which are characteristic for NCL or lysosomal impairment in brains of FTLD-TDP/GRN patients. Strikingly, saposin D, SCMAS as well as the lysosomal proteins CTSD and LAMP1/2 are all elevated in patients with FTLD-TDP/GRN. Thus, our findings suggest that lysosomal storage disorders and GRN-associated FTLD may share common features.

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Acknowledgments

We thank Paul Saftig (Christian-Albrechts University of Kiel) for providing the Ctsd knockout mouse strain, Masugi Nishihara (University of Tokyo) for the Grn knockout mouse strain, Konrad Sandhoff (University of Bonn, Kekulé-Institut für Organische Chemie und Biochemie) for the saposin D antibody, Elizabeth Neufeld (University of California Los Angeles) for the SCMAS antibody and Virginia Lee and Alice Chen-Plotkin (University of Pennsylvania) for the TMEM106B antibody clone N2077. We are grateful to Andrea Wenninger-Weinzierl and Brigitte Kraft for excellent technical assistance and to Dorothee Dormann for critical reading of the manuscript and valuable comments. This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 321366-Amyloid (advanced grant to C.H.) and the Competence Network for Neurodegenerative Diseases (KNDD) of the Bundesministerium für Bildung und Forschung (BMBF to C.H.). J.K.G. is supported by the RTG1373 (DFG) and C.M.L. by the Hans & Ilse Breuer foundation. The Antwerp site was in part funded by the MetLife Foundation Award (to C.V.B.), the Belgian Science Policy Office Interuniversity Attraction Poles Program, the Medical Foundation Queen Elisabeth, the Foundation for Alzheimer Research (SAO/FRA), Flemish Government initiated Methusalem Excellence program, the Agency for Innovation by Science and Technology (IWT) Flanders, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund. We acknowledge the contribution of genetic data by I. Gijselinck and M. Cruts, clinical and pathological data by the neurologists T. Van Langenhove, P. Cras, P.P. De Deyn and immunohistochemical data, autopsy brain samples and sections by the neuropathologist by A. Sieben. We are also grateful for the support by the research nurses at VIB, the personnel at the neurological departments at the Antwerp University Hospital and ZNA Middelheim, the Antwerp Biobank at the Institute Born-Bunge and the Genetic Service Facility at VIB. J.J. receives a Ph.D. fellowship of the IWT. We acknowledge the London Neurodegenerative Disease Brain Bank and Brains for Dementia Research, the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, Los Angeles, CA 90073, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society and the Veterans Affairs West Los Angeles Healthcare Center for providing brain tissue. We thank the Batten Disease Registry, Genetic Services and Specialty Clinical Laboratories, NYS Institute for Basic Research in Developmental Disabilities.

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  1. Adolf-Butenandt Institute, Biochemistry, Ludwig-Maximilians-University Munich, Schillerstrasse 44, 80336, Munich, Germany

    Julia K. Götzl, Kohji Mori, Katrin Fellerer, Gernot Kleinberger, Christina M. Lang, Christian Haass & Anja Capell

  2. Institute of Neuroscience, Technical University Munich, 80802, Munich, Germany

    Julia K. Götzl

  3. Department of Biochemistry, Christian-Albrechts-University Kiel, 20498, Kiel, Germany

    Markus Damme

  4. German Center for Neurodegenerative Diseases (DZNE) Munich, 80336, Munich, Germany

    Sabina Tahirovic, Elisabeth Kremmer, Thomas Arzberger & Christian Haass

  5. Munich Cluster for Systems Neurology (SyNergy), 80336, Munich, Germany

    Gernot Kleinberger & Christian Haass

  6. Department of Molecular Genetics, Neurodegenerative Brain Disease Group, VIB, 2610, Antwerp, Belgium

    Gernot Kleinberger, Jonathan Janssens, Julie van der Zee & Christine Van Broeckhoven

  7. Institute Born-Bunge, University of Antwerp, 2610, Antwerp, Belgium

    Gernot Kleinberger, Jonathan Janssens, Julie van der Zee, Jean-Jacques Martin, Sebastiaan Engelborghs & Christine Van Broeckhoven

  8. Institute of Molecular Immunology, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), 81377, Munich, Germany

    Elisabeth Kremmer

  9. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany

    Hans A. Kretzschmar & Thomas Arzberger

  10. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, 80336, Munich, Germany

    Thomas Arzberger

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Götzl, J.K., Mori, K., Damme, M. et al. Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127, 845–860 (2014). https://doi.org/10.1007/s00401-014-1262-6

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