Progranulin and Frontotemporal Lobar Degeneration

Abstract

Granulin (GRN) mutations were first found in frontotemporal dementia (FTD) patients with ubiquitin-positive, tau-negative inclusions in 2006. These inclusions were also found to contain a TAR-DNA binding protein of 43 kDa (TDP-43). PGRN protein itself is not a component of ubiquitin-positive inclusion bodies. Since then, more than 190 GRN mutations have been reported, including substitutions, insertions, and deletions. The common pathological mechanism observed with these mutations was proposed to arise from haploinsufficiency; the amount of functional PGRN was reduced to half of the normal level. In fact, GRN mutation carriers showed significantly reduced expression levels of PGRN in plasma and serum. Immunohistochemical analyses of phosphorylated TDP-43 revealed that cases of FTLD-TDP with a GRN mutation invariably display type A pathology, which is characterized by numerous short dystrophic neurites (DNs) and crescentic or oval shaped neuronal cytoplasmic inclusions (NCIs). GRN mutations were initially found in FTD patients with tau-negative, TDP-43-positive inclusions, however, recent findings suggested that different clinical phenotypes may be seen in the same GRN mutation carriers and additional tau or α-synuclein accumulation may be observed.