The Role of Progranulin in Frontotemporal Dementia
type: CreativeWork
description: Frontotemporal dementia (FTD) is one of the most common forms of presenile dementia with a cost per patient per year greater than Alzheimer's disease. FTD is a highly heritable disease, and one of the most common genetic causes is heterozygous loss-of-function mutations in GRN, the gene that encodes the protein progranulin. In order to treat GRN-FTD, our lab developed small molecule enhancers of GRN expression which boost progranulin back to healthy levels. However, there was no robust phenotype in progranulin haploinsufficient models against which to test our progranulin enhancing drugs. To this end, I utilized a technique called LysoIP followed by tandem-mass-tag mass spectrometry to define robust lysosomal proteomic aberrations in progranulin haploinsufficient cells in both Grn heterozygous mouse models as well as GRN-FTD patient derived fibroblasts. This led to the discovery that progranulin haploinsufficiency leads to decreases in dozens of lysosomal proteins whose complete loss-of-function mutations lead to lysosomal storage disorders. I further utilized our lead compound to correct this aberrant lysosomal proteome in both mouse and human cells, restoring key lysosomal proteins to control levels and demonstrating the capability of our drug to not only boost progranulin, but to boost overall lysosomal biogenesis as well.
abstract: Frontotemporal dementia (FTD) is one of the most common forms of presenile dementia with a cost per patient per year greater than Alzheimer's disease. FTD is a highly heritable disease, and one of the most common genetic causes is heterozygous loss-of-function mutations in GRN, the gene that encodes the protein progranulin. In order to treat GRN-FTD, our lab developed small molecule enhancers of GRN expression which boost progranulin back to healthy levels. However, there was no robust phenotype in progranulin haploinsufficient models against which to test our progranulin enhancing drugs. To this end, I utilized a technique called LysoIP followed by tandem-mass-tag mass spectrometry to define robust lysosomal proteomic aberrations in progranulin haploinsufficient cells in both Grn heterozygous mouse models as well as GRN-FTD patient derived fibroblasts. This led to the discovery that progranulin haploinsufficiency leads to decreases in dozens of lysosomal proteins whose complete loss-of-function mutations lead to lysosomal storage disorders. I further utilized our lead compound to correct this aberrant lysosomal proteome in both mouse and human cells, restoring key lysosomal proteins to control levels and demonstrating the capability of our drug to not only boost progranulin, but to boost overall lysosomal biogenesis as well.
author: Werthmann, Gordon Chandler
language: en
keywords: Intercellular Signaling Peptides and Proteins, Lysosomes, Progranulins, Frontotemporal Dementia
date published: 2025-09-08T21:51:16Z
date modified: 2026-07-24T05:52:08Z
provider: University of Texas Southwestern Medical Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Southwestern Medical Center

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152.5/10712