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Lysosomal Dysfunction and Other Pathomechanisms in FTLD: Evidence from Progranulin Genetics and Biology

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Frontotemporal Dementias

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1281))

Abstract

It has been more than a decade since heterozygous loss-of-function mutations in the progranulin gene (GRN) were first identified as an important genetic cause of frontotemporal lobar degeneration (FTLD). Due to the highly diverse biological functions of the progranulin (PGRN) protein, encoded by GRN, multiple possible disease mechanisms have been proposed. Early work focused on the neurotrophic properties of PGRN and its role in the inflammatory response. However, since the discovery of homozygous GRN mutations in patients with a lysosomal storage disorder, investigation into the possible roles of PGRN and its proteolytic cleavage products granulins, in lysosomal function and dysfunction, has taken center stage. In this chapter, we summarize the GRN mutational spectrum and its associated phenotypes followed by an in-depth discussion on the possible disease mechanisms implicated in FTLD-GRN. We conclude with key outstanding questions which urgently require answers to ensure safe and successful therapy development for GRN mutation carriers.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Xiaolai Zhou & Rosa Rademakers

  2. Department of Pharmacology and Chemical Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA

    Thomas Kukar

  3. VIB Center for Molecular Neurology, University of Antwerp-CDE, Antwerp, Belgium

    Rosa Rademakers

Authors
  1. Xiaolai Zhou
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  2. Thomas Kukar
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  3. Rosa Rademakers
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Corresponding author

Correspondence to Rosa Rademakers .

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Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA

    Bernardino Ghetti

  2. International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy

    Emanuele Buratti

  3. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Bradley Boeve

  4. VIB Center for Molecular Neurology University of Antwerp-CDE Antwerpen, Belgium, Department of Neuroscience Mayo Clinic Jacksonville, FL, USA, Antwerpen, Belgium

    Rosa Rademakers

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Zhou, X., Kukar, T., Rademakers, R. (2021). Lysosomal Dysfunction and Other Pathomechanisms in FTLD: Evidence from Progranulin Genetics and Biology. In: Ghetti, B., Buratti, E., Boeve, B., Rademakers, R. (eds) Frontotemporal Dementias . Advances in Experimental Medicine and Biology, vol 1281. Springer, Cham. https://doi.org/10.1007/978-3-030-51140-1_14

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