The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body.
Elastase, proteinase 3 and matrix metalloproteinase are proteases capable of cleaving progranulin into individual granulin peptides.
[9] Progranulin is expressed in a wide variety of cell types both in the periphery and in the central nervous system.
[9] The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked β-sheet configuration.
Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability.
[18] A recent mice study suggests that progranulin may be involved in regulating the early development of cerebellar tissue by selecting for individual climbing fibers as they intersect and form synapses with Purkinje cells.
[19] In addition, several studies implicate progranulin in synaptic pruning, a microglial process that occurs during development of the neural network.
[10] In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the glycogen synthase kinase-3 beta.
Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization.
[11] Progranulin expression is regulated by TFEB, a transcription factor that mediates proteins involved in lysosomal biosynthesis.
[15][8][9] Patients with the heterozygote mutation exhibit a reduction of 70–80% serum progranulin levels when compared to controls.
[15] Reprogrammed stem cells restore GRN mRNA levels to 50%, further suggesting that some other genetic or environmental factor is involved in regulating FTD disease expression.
[9] Human FTLD-GRN derived fibroblasts show decrease lysosomal protease activity and lymphoblasts containing neuronal ceroid lipofuscinosis-like storage material.
[9] FTLD-GRN IPSC cortical Neurons have enlarged vesicles, lipofuscin accumulation and cathepsin D deficiency.
[9] Homozygous mutation of the GRN gene causes neuronal ceroid lipofuscinosis (NCL) characterized by an accumulation of autofluorescent lipofuscin, enlarged vacuoles, impairment in lysosomal activity, retinal and brain degeneration, exaggerated inflammatory responses, microgliosis, astrogliosis and behavioral dysfunction such as OCD-like and disinhibition-like behavior.
[15][9] Aged GRN double mutant mice have lipofuscin deposits and enlarge lysosomes, while one group found phosphorylated TDP-43.
[25] Progranulin can promote cyclin D1 expression in breast cancer lines and phosphorylation of proteins through extracellular regulated kinase signaling pathways.