Identification and Study of Genetic Regulators of Progranulin
A sample of progranulin, a protein known to go awry in FTLD-TDP.
Given that deficiencies in progranulin protein cause frontotemporal lobar degeneration (FLTD) with TDP-43 pathology (FTLD-TDP), the Frontotemporal Dementia and Related Disorders Laboratory seeks to determine how progranulin levels are regulated, thereby facilitating the development of novel treatments and therapies for FTLD-TDP and related TDP-43 proteinopathies.
Mutations in the progranulin gene (GRN) cause FTLD-TDP and individuals with GRN mutations have a 50 percent reduction in functional progranulin protein (PGRN). Since 2010 the laboratory has contributed significantly to understanding of PGRN biology by identifying proteins involved in the regulation of PGRN levels or function. Using unbiased genome-wide association studies, the team successfully identified the multiligand receptor sortilin 1, the uncharacterized transmembrane protein 106B (TMEM106B) and, more recently, the lysosomal protein prosaposin as PGRN regulators.
The study and identification of these PGRN regulators continues to be a crucial step toward improved understanding of PGRN biology and determining whether these PGRN regulators can be therapeutically targeted to upregulate PGRN levels or improve function.
Another important line of research focuses on identifying a biomarker to measure FTLD risk and the efficacy of therapies designed to increase PGRN. Although the laboratory previously used enzyme-linked immunosorbent assays to show that plasma PGRN levels predict mutation status in GRN mutation carriers, recent work suggests that PGRN levels in the plasma of patient blood do not strongly correlate with PGRN levels in cerebrospinal fluid. In order to more accurately monitor disease treatment in the future, the laboratory is working to identify biomarkers in the plasma of patient blood for cases of FTLD-TDP that strongly correlates with the markers of PGRN-related disease in the cerebrospinal fluid.
The laboratory's current projects include:
- Determining the effect of a potential functional TMEM106B variant p.T185S on TMEM106B and PGRN in vitro and in vivo
- Identification and study of novel PGRN regulators by quantitative trait locus linkage mapping using whole-genome sequencing data and PGRN expression levels in human plasma
- Identification of plasma biomarkers co-regulated with PGRN using protein network analysis