Granulin is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''GRN''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Each granulin protein is cleaved from the precursor progranulin, a 593
amino-acid-long and 68.5
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
protein.
While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
* Photograph ...
,
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
,
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
and
protein homeostasis Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins ...
. The 2006 discovery of the GRN mutation in a population of patients with
frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.
Progranulin
Progranulin is the
precursor protein
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
for granulin. Cleavage of progranulin produces a variety of active 6 kDa granulin peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Cleavage of progranulin into granulin occurs either in the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
or the
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
.
Elastase
In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease.
Forms and classification
Eight human genes exist for elastase:
Some bacteria (includin ...
,
proteinase 3
Proteinase 3, also known as PRTN3, is an enzyme that in humans is encoded by the ''PRTN3'' gene.
Function
PRTN3 is a serine protease enzyme expressed mainly in neutrophil granulocytes. Its exact role in the function of the neutrophil is unknow ...
and
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
are
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s capable of cleaving progranulin into individual granulin peptides.
Progranulin and granulin can be further differentiated by their hypothesized opposing roles in the cell. While progranulin is associated with anti-
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, cleaved granulin peptides have been implicated in pro-
inflammatory behavior. A ''
C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' study showed that granulin peptides may also participate in toxic activity.
Expression
Progranulin is expressed in a wide variety of cell types both in the periphery and in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. Progranulin expression is low in early development, but increases as cells mature.
Cell types expressing progranulin include
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s,
microglia
Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
,
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
s and
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
.
Progranulin has been found to be highly expressed in
microglia
Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
and up-regulated during injury
Within the brain, progranulin mRNA is highly expressed in
pyramidal
A pyramid (from el, πυραμίς ') is a structure whose outer surfaces are triangular and converge to a single step at the top, making the shape roughly a pyramid in the geometric sense. The base of a pyramid can be trilateral, quadrilater ...
,
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
and
Purkinje cell
Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
Stru ...
s cells.
Structure
Each individual granulin domain peptide is 60 amino acids in length. Granulin peptides are
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
rich and capable of forming 6 disulfide bonds per residue.
The disulfide bonds form a central rod-like core that shuttles each individual granulin peptide into a stacked
β-sheet
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...
configuration.
The structure of the granulin protein is similar to the structure of proteins from protein families that consist of
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s,
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s,
ion channel modulator
A channel modulator, or ion channel modulator, is a type of drug which modulates ion channels. They include channel blockers and channel openers.
Direct modulators
Ion channels are typically categorised by gating mechanism and by the ion they con ...
s and
enzyme inhibitors
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
.
Because of progranulin's structural similarities to these proteins, much research was done to interrogate progranulin's potential role as a growth factor. When progranulin is secreted into the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
, it is often
glycosylated
Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...
at 4 confirmed and 1 tentative N-linked glycosylation sites.
The n-terminus of progranulin is hypothesized to be involved in the secretion of progranulin via secretory vesicles.
Specifically, Progranulin may be involved in regulating exosome excretion. The C-terminus of progranulin is hypothesized to be the primary binding partner of
SORT1
Sortilin (SORT1) is a protein that in humans is encoded by the ''SORT1'' gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitousl ...
, a receptor of extracellular progranulin.
The structural differences between each individual granulin peptide have yet to be characterized.
Interactive partners
In the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
, progranulin binds to receptors on several cell types resulting in either activation of a
signal transduction pathway
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
or engulfment into the cell. Several studies have shown progranulin's involvement in the binding of
SORT1
Sortilin (SORT1) is a protein that in humans is encoded by the ''SORT1'' gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitousl ...
and the subsequent trafficking of bounded progranulin to the
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
.
One recent study has shown that progranulin may actually mediate
prosaposin
Prosaposin, also known as PSAP, is a protein which in humans is encoded by the ''PSAP'' gene.
This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator Pr ...
trafficking to the lysosome via
SORT1
Sortilin (SORT1) is a protein that in humans is encoded by the ''SORT1'' gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitousl ...
. However, the absence of
SORT1
Sortilin (SORT1) is a protein that in humans is encoded by the ''SORT1'' gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitousl ...
does not prevent exogenous progranulin from promoting neurite outgrowth or enhancing cell survival of GRN knockout cells, suggesting that other receptors are involved in mediating extracellular progranulin function
For example,
SORT1
Sortilin (SORT1) is a protein that in humans is encoded by the ''SORT1'' gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitousl ...
-/- neuronal cells are still able to bind progranulin.
Other studies have suggested
tumor necrosis factor
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
and
EPH receptor A2
EPH receptor A2 (ephrin type-A receptor 2) is a protein that in humans is encoded by the ''EPHA2'' gene.
Function
This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have bee ...
as potential progranulin facilitators.
After binding to the receptor, progranulin may induce and modulate signaling pathways such as
MAPK/ERK
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling ...
,
PI3K/Akt, and
FAK.
Gene ontology
The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species. More specifically, the project aims to: 1) maintain and develop its controlled vocabulary of gene and g ...
enrichment analysis reveals an association between progranulin and
notch receptor __NOTOC__
__FORCETOC__
Notch proteins are a family of type-1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain mediates interactions with DSL fa ...
signaling.
Granulin has also been shown to interact with Cyclin T1
and TRIB3.
Function
Development
Although progranulin expression increases as cells mature,
they are still involved in the development of multiple cell types. Progranulin is hypothesized to be a
neurotrophic factor
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...
involved in
corticogenisis. Induced pluripotent stem cell lines (IPSC) harboring the GRN mutation show a decrease in cortical neuronal differentiation ability. A recent mice study suggests that progranulin may be involved in regulating the early development of
cerebellar
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
tissue by selecting for individual
climbing fiber
Climbing fibers are the name given to a series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata.
These axons pass through the pons and enter the cerebellum via the inferior cerebellar peduncle whe ...
s as they intersect and form
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s with
Purkinje cell
Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
Stru ...
s. In addition, several studies implicate progranulin in
synaptic pruning
Synaptic pruning, a phase in the development of the nervous system, is the process of synapse elimination that occurs between early childhood and the onset of puberty in many mammals, including humans. Pruning starts near the time of birth and con ...
, a microglial process that occurs during development of the neural network.
Cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s, a neuronal marker for synapse elimination, is found to be upregulated in neurons with the GRN mutation.
Increased cytokine tagging results in an increase in microglial density and activity around
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s.
Progranulin may also be involved in sexual determination during
embryonic
Embryonic may refer to:
*Of or relating to an embryo
* ''Embryonic'' (album), a 2009 studio album by the Flaming Lips
*''Embryonics
''Embryonics'' is a double-CD compilation of tracks by the Australian progressive metal band, Alchemist. It w ...
development.
Inflammation and wound healing
Progranulin levels are elevated when tissue is inflamed. After wounding,
keratinocyte
Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the stratum basale, basal layer (''str ...
s,
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s and
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s increase production of progranulin.
Neutrophils are capable of secreting
elastase
In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease.
Forms and classification
Eight human genes exist for elastase:
Some bacteria (includin ...
into the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
that is capable of cleaving progranulin into granulin peptides, that promote further promote
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
.
SLPI
Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the ''SLPI'' gene. SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in ...
, inhibitors of
elastase
In molecular biology, elastase is an enzyme from the class of ''proteases (peptidases)'' that break down proteins. In particular, it is a serine protease.
Forms and classification
Eight human genes exist for elastase:
Some bacteria (includin ...
, are also released by neutrophils and macrophages to modulate progranulin cleavage.
Addition of granulin B in cultured
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
cells causes cells to secrete
IL-8, a chemical that attracts
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s and neutrophils, which further suggests the involvement of granulin peptides in promoting
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
.
The addition of exogenous
SLPI
Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the ''SLPI'' gene. SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in ...
and progranulin is able to alleviate the enhanced inflammatory response of mice that are unable to inhibit the cleavage of progranulin.
Cell proliferation
Progranulin is highly expressed in cells that are highly proliferative in nature.
Several studies implicate progranulin in
tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
and neuronal outgrowth. Progranulin promotes
mitogenesis
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
in
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
cultures.
When two epithelial lines were cultured in media with recombinant PGRN, proliferation was stimulated.
Knockout of both progranulin homologues in a
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
model reduces
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
al outgrowth.
In primary
cortical and
motor neuron
A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...
s, progranulin regulates neuronal outgrowth and survival.
In primary motor neurons, progranulin has been shown to increase neurite outgrowth by regulating the
glycogen synthase kinase-3 beta.
Progranulin may function as an
autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
growth factor in
tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
.
Lysosomal function
The discovery of a GRN mutation leading to
lysosomal storage disorder
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
led to many studies that explored progranulin's role in regulating protein homeostasis via the
lysosomal
A lysosome () is a membrane-bound organelle found in many animal Cell (biology), cells. They are spherical Vesicle (biology and chemistry), vesicles that contain Hydrolysis, hydrolytic enzymes that can break down many kinds of biomolecules. A ly ...
pathway. Transcriptional gene network interference study suggests that progranulin is highly involved in lysosomal function and organization. Imaging studies have shown co-localization of progranulin and lysosomal marker
LAMP-1.
Progranulin expression is regulated by
TFEB
Transcription factor EB is a protein that in humans is encoded by the ''TFEB'' gene.
Function
TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane protei ...
, a transcription factor that mediates proteins involved in lysosomal biosynthesis.
Progranulin may be involved in regulating
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
activity. Proteases that could be regulated by progranulin include prosaposin, which is cleaved into saposin peptides in the
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
, and
cathepsin D
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
, the primary protease involved in protein aggregate break down.
GRN mutation shares similar neuropathology and clinical phenotype with
CHMP2B and
VCP mutations, genes that are both involved in the trafficking and breakdown of proteins involved in lysosomal function.
Clinical significance
Frontotemporal dementia
Heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutation of the GRN gene leading to progranulin haploinsufficiency causes
frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
.
These mutations include
frameshift
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
,
splice site
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' ba ...
, nonsense signal peptide,
Kozak sequence disruptions and
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
s, which result in either
nonsense-mediated decay
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...
or the production of non-functional protein.
Patients with GRN caused FTD (GRN-FTD) exhibit asymmetric brain
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
, although age of onset, disease progression and clinical symptoms vary, suggesting that other genetic or environmental factors may be involved in disease expression.
Pathological indicators include cytosolic
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
deposits enriched in hyperphosphorylated
TAR DNA-binding protein 43 (TDP-43),
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
-related protein aggregates, ubiquitin-binding protein p62,
lentiform intranuclear inclusions, dystrophic neurites and
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
.
Patients with the heterozygote mutation exhibit a reduction of 70-80%
serum progranulin levels when compared to controls.
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.
Mice exhibit reduced
autophagic
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
flux and
autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
-dependent clearance.
Human FTLD-GRN derived
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s show decrease lysosomal protease activity and
lymphoblast
__NOTOC__
A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen (from antigen-presenting cells) and increased in volume by nucleus and cytoplasm growth as well as new mRN ...
s containing neuronal ceroid lipofuscinosis-like storage material.
FTLD-GRN IPSC cortical
Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s have enlarged vesicles,
lipofuscin
Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retin ...
accumulation and
cathepsin D
Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...
deficiency.
Neuronal ceroid lipofuscinosis
Homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
mutation of the GRN gene causes
neuronal ceroid lipofuscinosis
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments ( lipofuscin) in the body's tissues. These ...
(NCL) characterized by an accumulation of autofluorescent
lipofuscin
Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retin ...
, enlarged
vacuole
A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...
s, impairment in
lysosomal
A lysosome () is a membrane-bound organelle found in many animal Cell (biology), cells. They are spherical Vesicle (biology and chemistry), vesicles that contain Hydrolysis, hydrolytic enzymes that can break down many kinds of biomolecules. A ly ...
activity, retinal & brain degeneration, exaggerated
inflammatory responses, microgliosis, astrogliosis and behavioral dysfunction such as
OCD-like and disinhibition-like behavior.
Aged GRN double mutant mice have
lipofuscin
Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retin ...
deposits and enlarge
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s, while one group found phosphorylated
TDP-43
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
.
Other diseases
Progranulin may also be involved in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
development,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
and other
metabolic disease
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS) and
limbic predominant age-related TDP-43 encephalopathy (LATE).
Progranulin can promote
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
expression in
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
lines and phosphorylation of proteins through extracellular regulated
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
signaling pathways.
Progranulin is highly expressed in
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
,
adrenal carcinomas and immortalized
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
cells.
There is a correlation between progranulin concentration and
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
severity.
Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer. The human liver fluke ''
Opisthorchis viverrini
''Opisthorchis viverrini'', common name Southeast Asian liver fluke, is a food-borne trematode parasite from the family Opisthorchiidae that infects the bile duct. People are infected after eating raw or undercooked fish. Infection with the par ...
'' contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.
Progranulin may also be involved in promoting the progression of
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
.
While progranulin may be anti-atherogenic, granulins may be pro-atherogenic.
Increased
serum and
plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
progranulin levels in patients with
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
and visceral
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
implicating progranulin in
metabolic diseases
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
.
A recent
genome-wide association study (GWAS) has found that genetic variations in ''GRN'' are associated with
late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations change the degradation pathways of misfolded protein contributing misfolded
β-amyloid
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
accumulation and plaque formation.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on GRN-Related Frontotemporal Dementia
{{PDB Gallery, geneid=2896
Protein families
Precursor proteins