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

Xiaolai Zhou, Thomas Kukar, Rosa Rademakers

Research output: Chapter in Book/Report/Conference proceedingChapter

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.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer
Pages219-242
Number of pages24
DOIs
StatePublished - 2021

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1281
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • Familial frontotemporal dementia
  • Genetic modifier
  • Granulins
  • Inflammation
  • Lysosomal dysfunction
  • Lysosome
  • Neurotrophic factor
  • Progranulin
  • TMEM106B

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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