Progranulin: Mutation and Regulation in Neurodegenerative Diseases


Reduced levels of GRN cause FTLD and may predispose to neurodegeneration. On the other hand, GRN levels are up-regulated as part of the microglial response to neurodegeneration as shown by the accumulation of GRN (in green) around amyloid plaques (in red) in Alzheimer's disease transgenic mice.

In 2006, we identified mutations in the secreted growth factor progranulin (GRN) as a major cause of familial frontotemporal lobar degeneration with ubiquitin-positive and TDP43-positive neuronal inclusions (FTLD-TDP). Since then, we played an important role in the identification and characterization of mutations in GRN. GRN is cysteine-rich secreted glycoprotein which can be cleaved into a family of active 6 kDa peptides called granulins. Both GRN and the granulins are implicated in a range of biological processes including development, wound repair, inflammation and tumorigenesis. The roles of GRN in normal neuronal function and development of the central nervous system are still poorly understood, but it has been suggested that GRN may act as a neurotrophic factor.

To date, more than 60 different GRN mutations have been identified explaining the disease in 5-10 percent of all FTD patients and nearly 25 percent of familial FTD patients. All pathogenic mutations in GRN cause disease through a uniform disease mechanism i.e. the loss of 50 percent of functional GRN protein, causing the disease through haploinsufficiency. Our working hypothesis is that GRN haploinsufficiency — through multiple disease mechanisms — is a major cause of FTD while more subtle dysregulation of GRN may hold susceptibility to FTD and a wider range of neurodegenerative disorders.

Our current projects include:

  1. Identification of the complete spectrum and frequency of mutations in GRN using in-depth mutation screenings in well characterized patient populations
  2. Study of the role of GRN as a genetic risk factor in FTD and related disorders using genetic association studies
  3. Identification of genetic variants that are able to modify GRN expression using a genome-wide screening approach
  4. Study of the regulation of GRN by miRNAs

The identification of novel GRN loss-of-function mechanisms is relevant to fully appreciate the relative frequencies of GRN mutations in FTD and to increase molecular diagnostic accuracy and counseling. Unveiling the genetic and molecular pathways regulating GRN may further reveal novel targets that can be exploited for therapeutic actions aimed at delaying the neurodegenerative disease process.