Acta Neuropathologica

, Volume 127, Issue 6, pp 845–860

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

  • Julia K. Götzl
  • Kohji Mori
  • Markus Damme
  • Katrin Fellerer
  • Sabina Tahirovic
  • Gernot Kleinberger
  • Jonathan Janssens
  • Julie van der Zee
  • Christina M. Lang
  • Elisabeth Kremmer
  • Jean-Jacques Martin
  • Sebastiaan Engelborghs
  • Hans A. Kretzschmar
  • Thomas Arzberger
  • Christine Van Broeckhoven
  • Christian Haass
  • Anja Capell
Original Paper

DOI: 10.1007/s00401-014-1262-6

Cite this article as:
Götzl, J.K., Mori, K., Damme, M. et al. Acta Neuropathol (2014) 127: 845. doi:10.1007/s00401-014-1262-6

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.

Keywords

Frontotemporal lobar degeneration (FTLD)Progranulin (GRN)TDP-43Neuronal ceroid lipofuscinosis (NCL)Cathepsin DLysosomeNeurodegeneration

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Julia K. Götzl
    • 1
    • 2
  • Kohji Mori
    • 1
  • Markus Damme
    • 3
  • Katrin Fellerer
    • 1
  • Sabina Tahirovic
    • 4
  • Gernot Kleinberger
    • 1
    • 6
    • 7
    • 5
  • Jonathan Janssens
    • 6
    • 7
  • Julie van der Zee
    • 6
    • 7
  • Christina M. Lang
    • 1
  • Elisabeth Kremmer
    • 4
    • 8
  • Jean-Jacques Martin
    • 7
  • Sebastiaan Engelborghs
    • 7
  • Hans A. Kretzschmar
    • 9
  • Thomas Arzberger
    • 4
    • 9
    • 10
  • Christine Van Broeckhoven
    • 6
    • 7
  • Christian Haass
    • 1
    • 4
    • 5
  • Anja Capell
    • 1
  1. 1.Adolf-Butenandt Institute, BiochemistryLudwig-Maximilians-University MunichMunichGermany
  2. 2.Institute of NeuroscienceTechnical University MunichMunichGermany
  3. 3.Department of BiochemistryChristian-Albrechts-University KielKielGermany
  4. 4.German Center for Neurodegenerative Diseases (DZNE) MunichMunichGermany
  5. 5.Munich Cluster for Systems Neurology (SyNergy)MunichGermany
  6. 6.Department of Molecular GeneticsNeurodegenerative Brain Disease GroupAntwerpBelgium
  7. 7.Institute Born-BungeUniversity of AntwerpAntwerpBelgium
  8. 8.Institute of Molecular ImmunologyHelmholtz Center Munich, German Research Center for Environmental Health (GmbH)MunichGermany
  9. 9.Center for Neuropathology and Prion ResearchLudwig-Maximilians-University MunichMunichGermany
  10. 10.Department of Psychiatry and PsychotherapyLudwig-Maximilians-University MunichMunichGermany