Progranulin in frontotemporal lobar degeneration and neuroinflammation

Abstract

Progranulin (PGRN) is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD). Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs). While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration.

Figure 1

The protein sequence of full length PGRN and its proteolytically cleaved GRNs. Amino acids shown in bold represent the granulin consensus sequence separated by variably long linker regions. Cysteine-rich parts of the sequence are denoted by CC.

Figure 2

Immunohistochemical staining of human brain tissue using a PGRN-specific polyclonal antibody. In a neurologically normal individual, PGRN immunoreactivity is present in hippocampal pyramidal neurons, but particularly high in CA1 (A), dentate fascia (B) and endplate/CA4 (C). In AD, neurons and activated microglia (arrows) in the endplate are labeled (D), along with PGRN immunoreactivity associated with dystrophic neurites in senile plaques (inset).

Figure 3

Hypothetical interaction between PGRN, elastase and SLPI in the CNS. 1) PGRN expression in neurons in the absence of microglial-derived elastase has potentially growth factor and anti-inflammatory properties. 2) In response to CNS injury, microglia are activated and release inflammatory mediators, including proteases. 3) PGRN and elastase levels increase, resulting in the proteolytic cleavage of PGRN into GRNs, which may contribute to the inflammatory milieu. 4) Inflammatory signals such as IL-1β derived from activated microglia cause changes in nearby cells. 5) Astrocytes become reactive in response to inflammatory stimulus from activated microglia. 6) Reactive astrocytes produce SLPI, which along with its other anti-inflammatory properties, inhibits the proteolytic cleavage of PGRN into GRN as a means of feedback regulation of the inflammatory response.

Figure 4

Neuropathology of FTLD-U with PGRN mutations. Gross cortical atrophy is visible in frontal and superior temporal lobes (A). In coronal sections (B), the lateral ventricle is dilated and the caudate nucleus is flat (arrow). Laminar spongiosis in the layer II of the cortical ribbon (C) is associated with TDP-43-positive neuronal cytoplasmic (D, arrows) and "lentiform" intranuclear inclusions (inset). Severe neuronal loss (D) in these regions is associated with microgliosis (E) and astrogliosis (F), shown by a microglial marker [ionized calcium-binding adapter molecule 1 (Iba-1)) and glial fibrillary acidic protein (GFAP) specific immunohistochemistry, respectively.

Figure 5

Schematic model of nuclear trafficking of cyclin T1 and it alterations by PGRN and GRN. Cyclin T1 binds PGRN and some of its GRN derivatives when co-expressed in COS7 cells [91]. A) When cyclin T1 is expressed with full length PGRN, both proteins are localized in the cytoplasm. B) In contrast, when expressed with the C-terminal GRN, CDE, cyclin T1 and GRN are found in the nucleus, enabling down-stream transcription elongation. Given the evidence that PGRN and GRN are associated with translocation of proteins such as cyclin T1 from cytoplasm to nucleus, it is tempting to hypothesize that PGRN might be involved in similar regulation of TDP-43 nuclear-cytoplasmic translocation. With decreased functional PGRN in FTLD-U associated with PGRN mutations, TDP-43 translocation might be perturbed, leading to accumulation in the cytoplasm and formation of NCI.