The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

J Neurosci. 2015 Jun 24;35(25):9315-28. doi: 10.1523/JNEUROSCI.4808-14.2015.


Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies.

Keywords: C. elegans; TDP-43; frontotemporal lobar degeneration; granulin; neurodegenerative disease; progranulin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Progranulins
  • Real-Time Polymerase Chain Reaction
  • TDP-43 Proteinopathies / metabolism*
  • Zebrafish Proteins / metabolism


  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Zebrafish Proteins
  • progranulin A, zebrafish