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Minireviews:
Progranulin: A Proteolytically Processed
Protein at the Crossroads of Inflammation
and Neurodegeneration
Basar Cenik, Chantelle F. Sephton, Bercin
Kutluk Cenik, Joachim Herz and Gang Yu
J. Biol. Chem. 2012, 287:32298-32306.
doi: 10.1074/jbc.R112.399170 originally published online August 2, 2012
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MINIREVIEW
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 39, pp. 32298 –32306, September 21, 2012
© 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
Progranulin: A Proteolytically
Processed Protein at the
Crossroads of Inflammation and
Neurodegeneration*
Published, JBC Papers in Press, August 2, 2012, DOI 10.1074/jbc.R112.399170
Basar Cenik‡§, Chantelle F. Sephton‡, Bercin Kutluk Cenik¶,
Joachim Herz‡§储1, and Gang Yu‡2
From the Departments of ‡Neuroscience, §Molecular Genetics, and
储
Neurology and the ¶Hamon Center for Therapeutic Oncology Research,
University of Texas Southwestern Medical Center, Dallas, Texas 75390
Progranulin: The Basics
Progranulin (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 (11–13).
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
* This work was supported, in whole or in part, by National Institutes of Health
Grants HL63762 (to J. H.), HL20948 (to J. H.), and R01AG029547 (to G. Y.).
This work was also supported by the Consortium for Frontotemporal
Dementia Research, the Alzheimer’s Association, Welch Foundation Grant
I-1776, the American Health Assistance Foundation, the American Federation for Aging Research, and the Murchison Foundation.
1
To whom correspondence may be addressed. E-mail: joachim.herz@
utsouthwestern.edu.
2
To whom correspondence may be addressed. E-mail: gang.yu@
utsouthwestern.edu.
32298 JOURNAL OF BIOLOGICAL CHEMISTRY
Progranulin Haploinsufficiency Causes Frontotemporal
Lobar Degeneration with Ubiquitinated TDP-43-positive
Inclusions
In 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, hippocampal sclerosis, and atrophy of temporal and parietal lobes
are variably observed (20). The characteristic cellular pathology
is neuronal cytoplasmic inclusions and dystrophic neurites.
These inclusions are positive for TDP-43, an RNA-binding protein and splicing modulator that binds GRN mRNA (21, 22).
TDP-43 protein in these inclusions is ubiquitinated and hyperphosphorylated and may be proteolytically processed (23). Loss
of normal nuclear staining for TDP-43 is typical. Gliosis is also
commonly observed (Table 1).
In hereditary cases, the mode of inheritance is autosomal
dominant with incomplete penetrance (24, 25). Serum progranulin levels are lower in mutation carriers and patients
(lower than ⬃60 ng/ml) than in controls (higher than ⬃125
ng/ml) (26, 27). Based on the rationale that FTLD-TDP with
GRN mutations is caused by haploinsufficiency of progranulin,
small molecule enhancers of progranulin expression have been
pursued as potential treatments (28, 29).
Homozygous Progranulin Mutation Causes Neuronal
Ceroid Lipofuscinosis
Two homozygous GRN-deficient patients have been recently
reported (30). These patients presented with adult onset neuronal ceroid lipofuscinosis (NCL), suffering from progressive
loss of vision, retinal dystrophy, cerebellar ataxia, and seizures
(Table 1). Circulating progranulin was undetectable.
NCLs are genetic progressive lysosomal storage diseases
characterized by accumulation of lipofuscin (31). At least 10
related disorders are now classified as NCLs. Causative muta-
3
The abbreviations used are: FTLD, frontotemporal lobar degeneration; NCL,
neuronal ceroid lipofuscinosis; TNFR, TNF receptor; SLPI, secretory leukocyte protease inhibitor.
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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.
by the full-length protein, individual granulins, or both is not
clear. We begin our discussion with the consequences of progranulin deficiency.
MINIREVIEW: Progranulin and Neurodegeneration
TABLE 1
Comparison of two diseases caused by GRN mutations
Note that both FTLD-TDP and NCL may be caused by mutations in other genes. The information presented here applies only to cases with GRN mutations. For FTLD-TDP,
most common findings are listed; the clinical presentation and pathology can be heterogeneous.
FTLD-TDP with GRN mutations
NCL with GRN mutation
GRN mutations
Disease
Heterozygous loss of function, ⬎70 different mutations reported
Most common clinical
presentation
Macroscopic pathology
Microscopic pathology
Behavioral changes, language dysfunction
Homozygous loss of function, c.813_816del
(p.Thr272Serfs*10) reported in two
siblings
Vision loss, seizures
Severe frontotemporal cortical atrophy
Neuronal loss and gliosis, neuronal cytoplasmic and intranuclear
inclusions, dystrophic neurites, ubiquitinated phosphorylated
TDP-43 aggregates
Cerebellar atrophy
“Fingerprint profiles” seen by EM in skin
biopsy samples, brain pathology
unknown
CXCL1, IL-6, IL-12p40, and TNF-␣) in response to LPS, but
they express less IL-10. Microglia cultured from these animals
have toxic effects on co-cultured wild-type neurons. However,
the immunomodulatory role of progranulin in the periphery
may be different. In a recent study, Grn⫺/⫺ mice on a high fat
diet had reduced IL-6 concentrations in blood and adipose tissue. Interestingly, Grn ablation was protective against insulin
resistance (5). Finally, loss of the progranulin homolog results
in accelerated clearance of apoptotic cells in C. elegans (14) and
disruption of motor neuron development in zebrafish (39).
Mouse Models of Progranulin Deficiency
Several independent mouse lines with genetic Grn deletions
have been generated. Behaviorally, the most consistent finding
is social interaction deficits (33–35). In a classic test of hippocampal learning and memory (Morris water maze), Grn⫺/⫺
mice had mild deficits at old age (18 –21 months) in two studies
(33, 36) but no deficits at 8 months of age in another study (35).
Other reported behavioral deficits include depression-like
behavior and either increased (35, 37) or decreased (33) anxiety.
These behavioral phenotypes are fairly consistent with the clinical manifestations of FTLD, which include early behavioral
problems and later deficits in memory.
Histopathologically, robust microgliosis, astrogliosis, and
increased ubiquitin staining are observed in the brains of aged
Grn⫺/⫺ mice (7, 33–35, 38). Ahmed et al. (7) recently showed
that intracytoplasmic ubiquitinated aggregates observed in
these mice are probably composed of lipofuscin. This finding
was replicated in an independent Grn⫺/⫺ line (36). Although
some vacuolation was observed in the habenula and hippocampus in very old (23 months) Grn⫺/⫺ mice (7), overt neuronal
loss seems to be very mild or absent (34), in contrast with the
severe atrophy observed in human FTLD. Yin et al. (33)
observed increased staining with an antibody against phosphorylated TDP-43 in the brains of 18-month-old Grn⫺/⫺ mice;
however, none of the other studies detected overt TDP-43 proteinopathy. Wils et al. (36) recently reported somewhat
increased phospho-TDP-43 immunoreactivity in detergent-insoluble fractions of Grn⫺/⫺ mouse brains; nonetheless, they did
not detect a significant difference in TDP-43 staining by immunohistochemistry. Interestingly, none of these findings were
reported in heterozygous Grn⫹/⫺ mice, which would be analogous to the haploinsufficient condition in human FTLD-TDP.
Progranulin-deficient mice display dysregulated immune
responses in the brain (38) Macrophages from Grn⫺/⫺ mice
express higher levels of proinflammatory cytokines (MCP-1,
What Does Progranulin Do?
Reported biological activities of progranulin fall into three
broad categories: growth factor-like activities, modulation of
immune responses, and neuronal effects. Progranulin is overexpressed in many human and experimental tumors, including
carcinomas (40 – 43), gliomas (44), and sarcomas (45). It may
act akin to a growth factor, stimulating proliferation (46, 47),
survival (48), and invasion (49). Progranulin has been reported
to activate many of the typical cell proliferation signaling pathways, including ERK, PI3K, and Akt pathways (48, 50, 51), not
only in tumor cells but also in neurons (52, 53). Progranulin
may be a prognostic marker (54) or a therapeutic target in cancer: progranulin overexpression confers an aggressive phenotype to adenocarcinoma (46), immortalized ovarian epithelial
cells (55), breast cancer (49, 56), and hepatocellular carcinoma
(57), and anti-progranulin treatment reduces in vivo tumorigenicity of teratoma (58) and breast cancer cell lines (59). However, it should be emphasized that although these early studies
strongly linked progranulin to cancer, no cell surface receptor
has been shown to mediate these effects.
Full-length progranulin is generally anti-inflammatory;
whereas proteolytically released granulins may have the opposite effect (see below). Progranulin reduces reactive oxygen species production by immune complex-activated neutrophils (60)
and blocks TNF-␣-induced immune responses, namely respiratory burst, degranulation, and spreading of adherent human
neutrophils (61). Progranulin also attenuates TNF-␣-induced
IL-8 release (62). A recent finding suggests that these activities
may be mediated at the level of TNF receptors (TNFRs) (63).
Importantly, recombinant or proteolytically released granulins
do not antagonize TNF-␣.
Progranulin expression is induced by inflammatory stimuli
in astrocytes (64). Consistent with its immunomodulatory role,
progranulin expression was found to be induced in multiple
sclerosis, a classic example of neuroinflammation (65). How-
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tions occur in genes encoding lysosomal enzymes and several
incompletely characterized membrane proteins.
Lipofuscin is an aggregate of oxidized cross-linked proteins
and lipids. It can be toxic to cells by chelating metals, enhancing
oxidative damage, and inhibiting mitochondrial and lysosomal
function (32). Lipofuscin accumulation occurs during normal
aging but is greatly accelerated in NCLs. Interestingly,
increased accumulation of lipofuscin has not been reported in
cases of FTLD-TDP but has been detected in mouse models of
the disease (see below).
MINIREVIEW: Progranulin and Neurodegeneration
How Does Progranulin Affect Neurons?
An early study by Van Damme et al. (12) showed that progranulin induced neurite outgrowth. This has been replicated
by Gao et al. (53) but could not be replicated by Hu et al. (10).
Exogenous recombinant progranulin increased survival of
motor neurons in serum-free conditions in the study by Van
Damme et al., but knocking down progranulin to ⬃20% of normal levels did not affect survival of hippocampal neurons in
another study (70). Two recent studies investigated the effect of
progranulin deficiency on neuronal morphology and synaptic
transmission. Both genetic deletion of Grn in mice (35) and
siRNA-mediated knockdown of progranulin (70) led to
reduced dendritic length and reduced spine density in
hippocampal neurons. These results seem to support the
abovementioned neurite outgrowth-promoting effects of
progranulin.
Electrophysiologically, the ratio of field excitatory postsynaptic potential slope to afferent volley amplitude was diminished in hippocampal slices prepared from Grn⫺/⫺ mice (35).
This study also reported that induction of long-term potentiation in Grn⫺/⫺ slices was more difficult and that mean longterm potentiation amplitude (change in field excitatory postsynaptic potential slope) was diminished in Grn⫺/⫺ slices. The
authors interpreted these findings as suggesting reduced synaptic connectivity and impaired synaptic plasticity in Grn⫺/⫺
mice. However, the variation from slice to slice was large, especially in the Grn⫺/⫺ group.
Progranulin knockdown in cultured hippocampal neurons
resulted in reduced numbers of co-localized pre- and postsynaptic markers (i.e. reduced synapse density), an increased num-
32300 JOURNAL OF BIOLOGICAL CHEMISTRY
ber of synaptic vesicles per synapse (as revealed by electron
microscopy), and increased miniature excitatory postsynaptic
current frequency (70). This suggests decreased synaptic connectivity but enhanced transmission at individual synapses,
indicative of a homeostatic response.
What Is the Progranulin Receptor?
Progranulin has a classic N-terminal signal peptide and several N-glycosylation sites (71). It is readily secreted in cell culture and detected in serum and cerebrospinal fluid in animals.
Exogenous recombinant progranulin has many biological
effects as detailed above. Hence, several groups have searched
for progranulin receptors.
The first cell surface protein conclusively shown to bind progranulin was sortilin (10). Sortilin has diverse biological functions, including prosaposin trafficking to lysosomes (72),
hepatic VLDL secretion (73), and proneurotrophin-induced
apoptosis (74). It is a regulator of extracellular progranulin levels (75). Sortilin knock-out mice are grossly normal, have
increased levels of extracellular progranulin, and are resistant
to motor neuron injury (76). Sortilin does not seem to be a
signal-transducing receptor itself but acts as a coreceptor for
the low affinity neurotrophin receptor p75NTR. Neurotrophins
are overexpressed in cancer (77) and implicated in neurodegeneration and inflammation (78). Sortilin binds via the C terminus
of progranulin, suggesting that the C-terminal granulin domain
can potentially mediate the binding even after proteolytic
cleavage. However, the precise role of progranulin binding in
sortilin function remains unknown.
Perhaps the most interesting candidates for the elusive progranulin receptor are the TNFRs. In 2011, Tang et al. (63)
reported that progranulin bound to TNFRs with high affinity
and blocked the binding of TNF-␣. They also showed that progranulin or a synthetic progranulin fragment was therapeutic in
an arthritis model (63), essentially acting as an endogenous
TNF-␣ antagonist. Replication of these findings will be
immensely valuable to the field because TNF-␣ antagonism can
potentially explain most biological effects attributed to progranulin. Several lines of evidence, especially the knock-out
models, strongly suggest that progranulin has anti-inflammatory effects. Furthermore, Zhu et al. (61) previously reported
that full-length progranulin suppressed TNF-␣-induced neutrophil activation. Perhaps, progranulin haploinsufficiency
leads to an overabundance of TNF-␣ activity. However, it is
somewhat puzzling that an excess of TNF-␣ activity would lead
to a specific neurodegenerative phenotype rather than any of
the other inflammatory conditions associated with this cytokine (79), most notably arthritis. A recent report suggested that
the serum levels of IL-6, TNF-␣, and IL-18 were unchanged in
GRN mutation carriers compared with controls (although IL-6
levels were increased in symptomatic GRN mutation carriers)
(80). We are not aware of any published work detailing the
prevalence of a TNF-␣-related autoimmune disease (e.g. rheumatoid arthritis) in GRN mutation carriers or FTLD patients.
An epidemiologic study showing increased risk of inflammatory disease for individuals with progranulin deficiency will be
required to strengthen the hypothesis that progranulin is an
endogenous TNF-␣ antagonist.
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ever, no difference in cerebrospinal fluid progranulin levels was
reported in multiple sclerosis in an earlier study (66). Pickford
et al. (67) reported that progranulin may also be a chemotactic
cue for microglia. In this study, intracerebral injection of progranulin led to microgliosis in excess of that seen in a control
lesion. This is somewhat dissimilar to the knock-out studies
discussed above, where the deletion of progranulin was shown
to lead to gliosis. In contrast, Kessenbrock et al. (60) have
reported that recombinant progranulin reduced neutrophil
infiltration in a reverse passive Arthus reaction model. These
disparate results may perhaps be explained by differential in
vivo proteolysis of progranulin into proinflammatory granulins
or by differential effects on microglia and neutrophils.
Progranulin expression is stimulated in the early phases of
wound healing together with proinflammatory mediators (61).
In this context, progranulin may be an attractant for neutrophils, monocytes, fibroblasts, and endothelial cells. It also stimulates tube formation of endothelial cells (68). In mice with
genetic deletion of antileukoproteinase (secretory leukocyte
protease inhibitor (SLPI)), an inhibitor of progranulin degradation, exogenous progranulin was shown to enhance cutaneous
wound healing (61). Recently, progranulin was found necessary
for efficient activation of TLR9 (Toll-like receptor 9) by CpG
oligodeoxynucleotides (69). In this study, macrophages from
Grn⫺/⫺ mice had a muted response to CpG. However, it was
somewhat unclear whether full-length progranulin or granulins
mediated this effect.
MINIREVIEW: Progranulin and Neurodegeneration
Antagonism of TNF-␣ can potentially explain some of the
cancer-promoting effects of progranulin. TNF-␣ was first discovered as a humoral factor that caused rapid hemorrhagic
necrosis of experimental tumors. It is cytotoxic to several
tumor cell lines in vitro, increases endothelial permeability,
may stimulate an antitumor immune response, and is in clinical
use for immunotherapy of limb sarcomas (81). By overexpressing progranulin, a presumed TNF-␣ antagonist, tumors may
escape TNF-␣ toxicity. However, this hypothesis remains
untested.
TNF-␣ is involved in synaptic scaling, maintaining synapses
in a plastic state (82). After silencing, TNF-␣ enables up-regulation of surface AMPA receptor expression and miniature
excitatory postsynaptic current amplitudes (83). If progranulin
is acting as a TNF-␣ receptor antagonist at the synapse, we
would expect that progranulin deficiency would be functionally
equivalent to overabundance of TNF-␣. However, this does not
seem to be the case (70).
Unlike the case of full-length progranulin, no cell surface
receptor has been shown to mediate the biological effects of
proteolytically released granulins. Individual granulins do not
bind TNFRs, whereas only granulin E is expected to bind sortilin. A precursor protein being proteolytically processed into
active species is a relatively common mechanism in cellular
biology (e.g. TGF-␤ family of growth factors). We critically
examine the case of granulins below.
Proteolytic Cleavage of Progranulin and the Case of
Granulins
In the 1990s, several ⬃6-kDa granulin peptides were purified
from leukocyte granule extracts and bone marrow (84), kidney
(85), and various other biological sources (86). It was later discovered that all of these peptides are encoded by a single gene
(GRN) translated into a large precursor protein, progranulin
SEPTEMBER 21, 2012 • VOLUME 287 • NUMBER 39
(87). Granulins are released following proteolytic cleavage of
progranulin. Human progranulin contains seven full-length
granulin domains and one half-length granulin domain. These
granulins are named, from the N terminus of progranulin to the
C terminus, granulins p, G F, B, A, C, D, and E, with “p” denoting
the half-length “paragranulin” domain (Fig. 1). The molecular
structure of individual granulin domains has been solved. Each
granulin domain consists of parallel stacked ␤-hairpins held
together by six disulfide bonds (Fig. 1) (88, 89).
Progranulin is proteolytically cleaved by neutrophil elastase
(61), proteinase 3 (a neutrophil protease) (60), MMP-12 (matrix
metalloproteinase 12; macrophage elastase) (64), MMP-14
(90), and ADAMTS-7 (a disintegrin and metalloproteinase with
thrombospondin motifs 7) (91). Zhu et al. (61) have mapped the
neutrophil elastase cleavage sites and shown that cleavage
occurs in the linker regions between granulin domains. However, they did not detect any cleavage sites between granulins F,
B, and A (Fig. 1) even though granulins A and B had been individually purified from various sources. Notably, incubation of
recombinant progranulin with these proteases does not always
result in the release of solely 6 –12-kDa fragments as would be
expected if the ⬃80-kDa precursor protein was completely processed to 71⁄2 granulin domains. At least five intermediate products larger than 15 kDa seem to be present after overdigestion
with any of these proteases according to data presented previously (60, 61, 64). However, Kojima et al. (62) observed mostly
⬍6-kDa bands after 16 h of digestion at 37 °C with elastase.
After in vitro incubation with MMP-12, several fragments
(15– 45 kDa) were still detectable with an antibody against the
C terminus of progranulin (64).
SLPI protects progranulin from proteolysis by elastase. Interestingly, SLPI binds progranulin directly, and this interaction is
protective against proteolysis even when the active site of SLPI
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FIGURE 1. Schematic depicting the domain structure of progranulin. Boxed letters denote granulin domains. The NMR structure of granulin A according to
coordinates deposited by Tolkatchev et al. (89) (MMDB ID 63884) is shown on top. Disulfide bridges are shown in orange, ␤-sheets in yellow, and the peptide
backbone in green. Scissors denote elastase cleavage sites according to data presented by Zhu et al. (61). Asterisks denote linker regions where proteolytic
cleavage also takes place, but the protease that releases granulins A and B has not been conclusively identified. The amino acid sequence of granulin A is shown
at the bottom. Cysteines are highlighted in red. Numbers denote approximate positions of granulin domains relative to full-length human progranulin (593
residues).
MINIREVIEW: Progranulin and Neurodegeneration
is mutated (61). Apolipoprotein A-I similarly inhibits progranulin proteolysis (92).
Even though progranulin is known to be secreted and circulates in the full-length form in blood, proteolytic processing
probably takes places intracellularly to some extent. Progranulin cleavage products are detected in cellular fractions, and double deletion of neutrophil elastase and proteinase 3 increases
intracellular progranulin levels (60). MMP-12 cleaves progranulin intracellularly in microglia but not in conditioned
medium (64). An early study that identified an acrosomal glycoprotein later shown to be identical to progranulin also
showed that progranulin was partially proteolyzed as the sperm
moved along the epididymis (93). MMP-14 is active in the Golgi
apparatus, but the physiological significance of progranulin
cleavage by MMP-14 is undetermined.
Biological effects have been attributed to the granulin peptides. Granulin A has been reported to induce anchorage-independent growth of cultured keratinocytes and fibroblasts while
apparently inhibiting proliferation of other cancer cell lines (85,
87, 94). The effect of granulin B was generally inhibitory and
antagonistic to granulin A. At least in one case (87), fulllength progranulin did not have the same activity as granulin
A. An independent group reported that granulin D increased
DNA synthesis in cultured astrocytes and, to a limited
extent, in primary glioblastoma cells (44). Granulin E was
reported to act similarly to progranulin and to support neuronal survival in cell culture (12). Notably, purified recombinant granulins do not have the anti-inflammatory activities of full-length progranulin but, on the contrary, seem to
be proinflammatory (61). For example, elastase-digested
progranulin induced IL-8 release from A549 cells, whereas
recombinant granulin B induced IL-8 release from both
A549 and SW-13 cells.
32302 JOURNAL OF BIOLOGICAL CHEMISTRY
Perspectives
The number of distinct biological activities attributed to progranulin is remarkable. How can we reconcile these seemingly
nonspecific functions with the fact that progranulin deficiency
leads to two specific neurodegenerative conditions (FTLD in
the case of haploinsufficiency and NCL in the case of a homozygous mutation)? Progranulin is almost certainly a multifunctional protein, and multifunctional proteins are common in
eukaryotic organisms (95). Nevertheless, independent replication, particularly with cautious scrutiny toward impurities in
progranulin and granulin preparations, may whittle this large
number of biological activities down to a shorter list of bona
fide progranulin functions. Furthermore, we believe that granulin peptides are almost certainly bioactive and that a search for
granulin receptor(s) is warranted. Of particular interest is
whether the recombinant progranulin is proteolyzed in tissue
culture conditions, an observation that we feel has been insufficiently addressed.
Could GRN haploinsufficient FTLD-TDP and NCL with
homozygous GRN mutations be manifestations of the same
spectrum of diseases? In NCL, time of disease onset varies from
the neonatal period to young adulthood according to the
mutated gene, but patients with “mild” hypomorphic mutations are known to present with later onset than those with
“classic” loss-of-function mutations of the same genes (31). The
patients with homozygous loss-of-function mutations of progranulin reported previously (30) presented in their 20s, which
is quite late compared with other known NCL mutations. Perhaps, GRN haploinsufficient FTLD-TDP represents a very late
onset form of atypical NCL. This hypothesis seems to be supported by the mouse models: Grn⫺/⫺ mice display behavioral
characteristics of FTLD together with lipofuscinosis. However,
exaggerated lipofuscinosis has not yet been reported in FTLDVOLUME 287 • NUMBER 39 • SEPTEMBER 21, 2012
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FIGURE 2. Trafficking of prosaposin and progranulin. Both prosaposin and progranulin consist of several repeats of saposin and granulin domains, respectively (step 1). Both proteins are N-glycosylated (step 2) and secreted (step 3). Prosaposin is also directly transported to the lysosomes (Lys) via the mannose
6-phosphate receptor (step 4). Sortilin also plays a role in lysosomal trafficking of prosaposin (not shown). Reuptake of progranulin is mediated by sortilin,
whereas prosaposin reuptake is mediated by the LDL receptor-related protein (LRP), the mannose receptor (not shown), and the mannose 6-phosphate
receptor (not shown) (step 5). Both proteins are probably proteolyzed intracellularly, although this has not been shown directly for progranulin (step 6). In the
lysosome, the saposins activate lysosomal enzymes (pink pentagon) partly by lifting their substrates (green) out of the lipid bilayer (step 7). Lysosomal functions
of granulins remain unknown. Prosaposin is shown in blue, progranulin is shown in red. ER, endoplasmic reticulum.
MINIREVIEW: Progranulin and Neurodegeneration
Acknowledgments—We thank Daniel Dries, Can Cenik, and Gong
Chen for critical reading of the manuscript.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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TDP patient brains (or other tissues), in which the main ubiquitinated protein is known to be TDP-43. Furthermore, different regions of the brain seem to be primarily affected in FTLDTDP compared with NCL. Thus, it remains possible that
FTLD-TDP and GRN mutant NCL are caused by disruptions of
disparate pathways that are differentially sensitive to progranulin dosage.
Another relatively poorly understood concept is the role of
intracellular progranulin or granulins. Given the recent finding
of adult onset lysosomal storage disease caused by homozygous
progranulin deficiency and the high affinity binding between
progranulin and the lysosomal transport protein sortilin, an
essential intracellular role for progranulin in lysosomal biology
is a possibility. Moreover, another recently identified function
of progranulin/granulins, binding of CpG oligodeoxynucleotides to TLR9, takes place intracellularly in lysosomes. It is also
likely that proteolytic cleavage of progranulin into granulins
occurs in lysosomes (or somewhere along the way from the
endoplasmic reticulum to the lysosome). Could progranulin or
granulins be acting as activators or transporters of lysosomal
enzymes? Accumulation of the autophagy-related receptor p62
and the lysosomal protease cathepsin D was reported in Grn⫺/⫺
mice. Perhaps progranulin functions akin to prosaposin, which
is likewise synthesized as a precursor protein, secreted, and
taken up again into the cells, followed by proteolytic processing
into small (8 –11 kDa) bioactive saposin polypeptides (Fig. 2)
(96, 97). Saposins act as activators of lysosomal enzymes, and
genetic abnormalities of prosaposin cause lysosomal storage
disorders of varying severity. Lysosomal enzymes also play roles
in the regulation of immune responses, apoptosis, and defense
against pathogens (98, 99). Therefore, lysosomal functions of
progranulin/granulins could explain their immunomodulatory
properties. We believe that progress along these lines will ultimately lead to the identification of the biological mechanisms
underlying selective vulnerability of frontotemporal regions of
the brain to progranulin deficiency and, we hope, to novel drug
targets for the treatment of GRN-deficient conditions.
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