Brain progranulin expression in GRN-associated frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.

Progranulin expression is upregulated after spinal contusion in mice

“…In agreement with this timing, GRN colocalized with CD68, a marker enriched in activated macrophages and microglia. These results are consistent with activated microglia and macrophages being the predominant cellular sources of GRN expression in injured peripheral tissues [28, 59] and in the brains of individuals suffering from neurodegenerative disorders [3, 40], including frontotemporal lobar degeneration [4, 10, 36]. Although GRN is a modulator of macrophage proliferation [17], it also supports an anti-inflammatory phenotype of various cell types.…”

A NovelGRNMutation (GRNc.708+6_+9delTGAG) in Frontotemporal Lobar Degeneration With TDP-43–Positive Inclusions

“…The decrease in mRNA production, although not 50% of normal levels as is true for most GRN mutations, may behave like a haploinsufficiency, particularly if there are other factors affecting GRN transcript level, such as TMEM106B genotype. In addition, depending on the brain region on which the expression analysis performed, results may be higher than expected because expression may be reduced in unaffected regions but higher in affected regions because of either increased expression by the normal allele or expression by microglia (16). The in silico and in vitro splicing data provide a functional line of evidence for pathogenicity.…”

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

“…They are often characterized as frontotemporal lobar degeneration (FTLD-TDP) and generally increased expression of GRN is associated with pathogenesis. However, patients tend to have varying expression of GRN in the brain at late stages of disease [77]. In another study, neurons were characterized from a patient carrying a novel nonsense mutation in GRN (S116X) [66].…”