Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration

Abstract

GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin: The BasicsProgranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1-5). In the brain, intracellular expression is highest in neurons and activated microglia (6 -8). At the subcellular level, progranulin colocalizes with the endoplasmic reticulum and Golgi markers in the secretory pathway and the lysosomal marker Lamp1 (9, 10). Progranulin is a secreted glycoprotein and is readily detected in blood and cerebrospinal fluid (11)(12)(13).Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These "granulins" were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. Progranulin Haploinsufficiency Causes Frontotemporal Lobar Degeneration with Ubiquitinated TDP-43-positive InclusionsIn 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3 with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15,16). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5-15% of all dementias (17,18). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19).Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocam...

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

“…3 Proteolytic cleavage of this precursor protein by extracellular proteases gives rise to smaller peptide fragments termed granulins (GRNs) or epithelins. 5,6,34 Consistent with previous evidences implicating the aggressive inflammation and insulin resistance, 9,11,14 we demonstrated that PGRN treatment led to the attenuated insulin signaling and ER stress, which, in turn, contributes to insulin resistance and relates with inflammation.…”

“…[1][2][3][4] Recently, PGRN has emerges as a novel regulator associated with proinflammatory properties and insulin resistance. [5][6][7][8][9][10] Specifically, PGRN-deficient mice exhibited resistant to diet-induced obesity and insulin insensitivity through the modulation of inflammation, whereas adipocytes exposed to PGRN have increased susceptibility to be insulin-resistant.…”

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

“…6A). Interestingly, PGRN, a protein found within the lysosome lumen, the haploinsufficiency of which causes frontotemporal dementia in humans (29,30), also showed colocalization with LAMP1 in both neuronal cell bodies and at amyloid plaques ( Fig. 6 B and C and Fig.…”

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

“…Progranulin (PGRN), which is a 68.5-kDa glycoprotein containing 7.5 tandem repeats of a cysteine-rich motif, is proteolytically processed into 6-kDa granulins (GRNs) [1]. PGRN is involved in multiple physiological functions and various disease processes, including autoimmune disorders, tumorigenesis, and insulin resistance [2][3][4].…”