Traffic 2011; 12: 948–955
© 2011 John Wiley & Sons A/S
doi:10.1111/j.1600-0854.2011.01188.x
Review
Physiology and Pathology of Endosome-to-Golgi
Retrograde Sorting
Christopher G. Burd
Department of Cell and Developmental Biology,
University of Pennsylvania School of Medicine,
Philadelphia, PA 19104-6058, USA,
cburd@mail.med.upenn.edu
Bidirectional traffic between the Golgi apparatus and
the endosomal system sustains the functions of the
trans -Golgi network (TGN) in secretion and organelle biogenesis. Export of cargo from the TGN via anterograde
trafficking pathways depletes the organelle of sorting
receptors, processing proteases, SNARE molecules, and
other factors, and these are subsequently retrieved from
endosomes via the retrograde pathway. Recent studies indicate that retrograde trafficking is vital to early
metazoan development, nutrient homeostasis, and for
processes that protect against Alzheimer’s and other
neurological diseases.
Key words: Alzheimer’s disease, Charcot-Marie-Tooth
disease, development, endocytosis, endosome, hereditary spastic paraplegia, retrograde, retromer, secretion,
sorting, trans -Golgi network
Received 31 January 2011, revised and accepted for
publication 5 March 2011, uncorrected manuscript
published online 7 March 2011, published online 8 April
2011
The endomembrane system of the eukaryotic cell is
constituted of the organelles of the secretory and
the endosomal-lysosomal (endo-lysosomal) systems. The
main functions of the secretory pathway are to enzymatically modify secretory cargo and to distribute it to
other organelles and the extracellular space. The primary
functions of the endo-lysosomal system are to internalize
extracellular molecules and components of the plasma
membrane and to sort them either to the lysosome
where they are degraded, or to other organelles for reuse.
The functional organization of the endomembrane system
depends critically on the accurate and efficient exchange
of molecules between the secretory and endo-lysosomal
systems. The trans-Golgi network (TGN) is the major sorting hub of the secretory pathway and the main site of
intersection with the endo-lysosomal system.
As secretory cargo is exported from the TGN, anterograde cargo sorting receptors and vesicle targeting and
fusion factors, such as SNAREs, are depleted from the
TGN and must be replenished to sustain TGN function.
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Retrograde transport returns these factors to the TGN
from the endo-lysosomal system for reuse (Figure 1). A
catalog of factors that functions in endosome-to-TGN retrograde transport has been in hand for several years
now (1,2), and the mechanisms by which these factors
function in retrograde sorting and export from the endosome are beginning to be elucidated. In addition to these
advances regarding sorting and trafficking mechanisms,
recent developments have begun to illuminate roles of the
endo-lysosomal system in cell physiology, development of
multi-cellular organisms, and human disease (Table 1). In
this review I discuss these emerging themes in endosomal
retrograde trafficking research.
Retrograde Pathway Cargoes
Endosomal retrograde cargoes vary considerably in their
structures and functions, though they can be broadly
classified into four groups: (i) cargo sorting receptors, (ii)
integral membrane proteases, (iii) SNAREs and (iv) nutrient
transporters (1,2). In addition, some bacterial toxins (e.g.
Shiga toxin) constitute a class of exogenous retrograde
cargoes that harness the retrograde pathway to gain entry
into the cell and exert cytotoxicity (2).
TGN sorting receptors
One of the most abundant and best characterized retrograde cargoes of mammalian cells are the mannose
phosphate receptors (MPRs) (3). In the Golgi apparatus,
mannose 6-phosphate is incorporated into the carbohydrate chains that decorate soluble lysosomal acid hydrolases and it functions as a lysosomal targeting signal.
In the TGN, MPRs recognize mannose 6-phosphate and
serve to sort the acid hydrolases into clathrin-coated vesicles (CCVs) that bud from the TGN and ferry cargo to
the endo-lysosomal system (3). The more acidic lumenal
environment of the endosome (compared to the TGN)
favors dissociation of cargo from the receptors, which
are then returned to the TGN via the retrograde pathway.
Mutations that cripple the mannose 6-phosphate-based
sorting system result in disease because of the deficient
lysosome function (3).
The budding yeast Saccharomyces cerevisiae has been
enormously useful for investigating protein sorting in the
TGN and the endosomal retrograde pathway, although it
does not use mannose 6-phosphate as a signal for sorting to the lysosome-like vacuole. Instead, a different type
of sorting receptor, called Vps10, serves an analogous
Physiological Functions of the Retrograde Pathway
SNAREs
SNAREs mediate fusion of endosome-derived transport
carriers with the TGN, so they must be packaged with
retrograde cargo. In addition, the SNAREs that mediate
fusion of Golgi-derived vesicles with post-Golgi compartments must be returned to the TGN in order to sustain
anterograde trafficking. Genetic studies in yeast have shed
some light into retrograde sorting signals and the transacting factors that direct retrograde sorting of a limited
number of SNAREs. These signals are recognized by
sorting nexins and proteins containing ENTH domains
(8–11).
Figure 1: Endosomal sorting reactions. Endosomes are populated with cargo delivered by endocytosis and by anterograde
transport from the Golgi apparatus. In the endosome, cargo can
be sorted into the lysosomal degradation pathway via the multivesicular body (MVB), or it can be exported from the endosome
by the retrograde pathway. The TEN is the major sorting hub of
the retrograde pathway and it is the source of the tubular carriers
that ferry cargo to the trans-Golgi network.
function to the MPRs by binding sorting signals in newly
synthesized vacuolar resident proteins in the TGN (4).
Analysis of the requirements for endosome-to-TGN
retrieval of Vps10 led to the discovery of retromer (5,6), a
conserved sorting device that functions at the endosome
to sort cargo into the endosomal retrograde pathway.
Vps10 is the founding member of a family of Vps10-related
sorting receptors that is present in most (but not all)
eukaryotic cells (7). The functions of vertebrate Vps10
proteins have diverged considerably from the role of
yeast Vps10 in TGN-to-endosome sorting to include functions in endocytosis and intracellular signaling, and they
have been implicated in diverse diseases, including late
onset Alzheimer’s disease (AD) and other diseases of
the nervous system, coronary artery disease and type II
diabetes (7). From a trafficking perspective, Sortilin and
SorLA are the best characterized human Vps10 family proteins, with sorting signals identified in their cytoplasmic
domains that confer sorting into CCVs at the TGN and at
the plasma membrane.
Integral membrane proteases
Some members of the proprotein convertase family,
the archetypes being human furin and yeast Kex2,
cycle between the TGN and the endo-lysosomal system.
These enzymes are type I integral membrane proteins
constituted of a lumenal protease domain that processes
pro-hormones and other proteins, a single membrane
spanning segment, and a cytoplasmic domain that
contains anterograde and retrograde sorting signals.
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Nutrient transporters
Some nutrient transporters cycle between the Golgi
apparatus and the plasma membrane, relying on the
endosomal retrograde pathway to be returned to the TGN
after internalization from the plasma membrane. These
cargoes are discussed in detail in the section entitled
Physiological Functions of the Retrograde Pathway.
Sorting into the Retrograde Pathway
A key feature of the endosomal system is the tubular endosomal network (TEN) that constitutes the major sorting
station of the retrograde pathway (Figure 1). An important
distinction between the vacuolar and tubular domains of
an endosome is that the vacuolar domain is characterized
by relatively low membrane curvature and large lumenal
volume, while the TEN is characterized by high relative
membrane curvature and low lumenal volume. Due to the
larger capacity of a tubule versus a vacuole (i.e. a sphere)
to partition membrane constituents from lumenal content (12), the TEN is well suited for exporting cargo from
the endo-lysosomal system, and many retrograde sorting
devices promote sorting of cargo into the TEN (1,2). Fission of these tubules produces the carriers that mediate
retrograde transport.
A retrograde sorting device called ‘retromer’ has been
found to provide critical functions during early development and for normal cell physiology (13). Retromer is
a multi-protein complex whose components recognize
retrograde cargo, promote sorting into the TEN, and
microtubule-dependent transport of cargo carriers to the
TGN (14). On the endosome membrane, retromer contains a dimer of sorting nexins that each contains a
phosphatidylinositol 3-phosphate PHOX (PX) homology
domain and a Bin-Amphyphisin-Rvs (BAR) domain implicated in recognition of high-curvature membranes, such
as those that comprise the TEN. Three other retromer subunits, Vps26, Vps29 and Vps35, assemble into a stable
sub-complex (‘Vps26/29/35’) that is implicated in recognition of retrograde cargo (14). The physical basis of cargo
recognition by retromer is not well understood, though
several retromer-dependent sorting signals conform to a
short motif: – X – φ (‘’ indicates an aromatic residue,
‘X’ indicates any residue, φ indicates a hydrophobic
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Table 1: Retrograde cargoes and sorting factors in disease and development
Protein name
Cargo
APP
Sortilin
SorLA
β site APP cleavage
enzyme (BACE)
DMT1 (human)
Fet3-Ftr1 (yeast)
Wntless (Wls)
Sorting factors Rab7
Functional class
Retrograde
sorting factors
Physiological function
Type I integral membrane
protein
Sorting receptor
Unknown; proteolytic product
(Aβ) is linked to AD
• TGN sorting (anterograde)
• Endocytosis
• Biogenesis of ‘IRVs’
SorLA, retromer,
Snx17
Retromer
Sorting receptor
Protease
Unknown
APP processing; AD
Retromer
Retromer, GGA
Nutrient transporter
Nutrient transporter
Wnt sorting receptor
Iron transport
Iron transport
Required for Wnt signaling
during development
Retromer
Retromer, Snx3
Retromer
Rab GTPase
• Endosome maturation
• Endosome recruitment of
retromer
• Late endosome motility
Strumpellin
Unknown
Vps26, Vps35 (retromer)
Sorting factor
residue). Endosomal clathrin and clathrin adapter proteins
co-operate with retromer for full efficiency of retrograde
sorting (15) and it is likely that other retrograde sorting
factors remain to be discovered.
Physiological Functions of the Retrograde
Pathway
Maintenance of insulin-regulated trafficking
In adipocytes and skeletal muscle, insulin signaling results
in the recruitment of the major insulin responsive glucose transporter, GLUT4, to the plasma membrane. In
the basal state, GLUT4 and a small cadre of other proteins are sequestered within the cell in ‘insulin responsive
vesicles’ (IRVs; also called ‘GLUT4 storage compartment,’
GSC) that are produced from the TGN (16). A Vps10 family
sorting receptor that cycles between the TGN and endosomes, Sortilin, is an abundant component of IRVs (17)
and is essential for their formation (18). After insulinstimulated exocytosis, IRV proteins are internalized from
the plasma membrane and then sorted via the retrograde pathway to the recycling endosome and/or the TGN
where IRVs are then reassembled (19). Efficient and accurate retrograde sorting is, therefore, essential for glucose
homeostasis through its role in sustaining reassembly
of IRVs. Export of GLUT4 and the cation-independent
MPR, a minor component of IRVs, from the endosome
was recently shown to depend on CHC22, an isoform
of clathrin heavy chain that localizes, in part, to endosomes (20,21). CHC22 associates with the Snx5 retromer
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Component of WASH F-actin
regulatory complex
Lower expression in brain
correlated with AD
Mutations affect
retromer-dependent
sorting
Associated with
retromer
Retromer
sorting nexin subunit (22), suggesting that retromer is a
key sorting device that sustains IRV reassembly.
Metabolic regulation of retrograde sorting
Steady-state localization of certain nutrient transporters is
regulated by metabolic cues. This regulation optimizes
nutrient uptake capacity, contributes to intracellular
nutrient homeostasis and also protects the cell from
accumulating toxic amounts of nutrients.
In yeast, the high-affinity reductive iron transporter,
composed of a complex of the Fet3 copper oxidase
and the Ftr1 iron permease, localizes to the plasma
membrane of cells that are starved for iron, and it is
rapidly internalized by endocytosis and sorted to the
vacuole where it is degraded when iron is added to the
growth medium (23–25). In iron-starved cells, Fet3-Ftr1 is
internalized via bulk endocytosis and is then returned
to the Golgi via the retrograde pathway to be ‘resecreted’, thereby maintaining the transporter on the
plasma membrane. A possible reason that Fet3-Ftr1 is
sorted through the Golgi in iron-starved cells is that the
Fet3 subunit is loaded with copper in the Golgi, so this
sorting step ensures that Fet3 is fully functional during
nutrient stress. A genetic analysis of the requirements
for plasma membrane localization of Fet3-Ftr1 under iron
starvation conditions revealed a requirement for retromer
and the Snx3 sorting nexin (also called Grd19) (24). In
these mutants, internalized Fet3-Ftr1 fails to be sorted
into the retrograde pathway and is delivered to the vacuole
and degraded, resulting in a reduction in the amount of the
transporter on the plasma membrane. Snx3 had previously
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Physiological Functions of the Retrograde Pathway
been implicated in maintaining TGN residence of the
Ste13 integral membrane protease that cycles between
the TGN and the endo-lysosomal system, and it recognizes
retrograde sorting signals in Ste13 and Fet3-Ftr1 (24,26).
Snx3 associates with retromer (24,27), leading to the
proposal that it functions as a cargo adapter for retromermediated export from the endosome (24). Snx3 is a
member of the so-called ‘PX-only’ sorting nexins, being
composed of a PX domain and a short amino terminal
extension, and it will be interesting to determine if any of
the other PX-only sorting nexins (a total of 10 are encoded
in the human genome) function in an analogous manner.
Retromer plays a key role in trafficking of a human divalent metal ion transporter, DMT1, that mediates uptake
of divalent metal ions, including iron. Alternative splicing
of DMT1 pre-mRNA generates two forms of DMT that
localize to distinct endosomal compartments (28). One
form, called DMT1-II, colocalizes with internalized transferrin receptor (TfR) and mediates transport of iron from
the lumen of this endosome into the cytosol. Although
the functions of TfR and DMT1-II are coupled, sorting of
DMT1-II and TfR diverges at the early endosome; internalized TfR is returned to the plasma membrane, but DMT1-II
is exported by retromer from the endosome to the TGN
and then it is delivered back to the plasma membrane (29).
Divergent sorting of TfR and DMT1-II may provide a mechanism to regulate cytosolic iron which must be tightly controlled to avoid toxicity. The conserved function retromer in
mediating retrograde sorting of iron transporters in human
and yeast cells highlights how the retrograde pathway is
harnessed to maintain nutrient homeostasis.
mutants because of turnover in the lysosome. Importantly,
a second mutation that blocks endocytosis or delivery
to the lysosome stabilizes Wls protein level, but the
developmental defects are not rescued in double mutant
animals (31,33,35). Together, these results indicate that
Wls performs an essential function at the TGN and suggest that newly synthesized Wnt encounters Wls in the
Golgi apparatus, where they form a complex (31,32). Thus,
Wls appears to function as a sorting receptor for Wnt in
the TGN and then escorts Wnt to the plasma membrane
where it may facilitate Wnt release from the cell. Wls
is then internalized by endocytosis and then sorted in a
retromer-dependent manner to the TGN to sustain Wnt
secretion. By controlling the total amount of Wls and the
abundance of Wls in the TGN, the retrograde pathway
provides a post-translational mechanism that can provide
fine regulation of the Wnt regulatory axis.
Retrograde Sorting in Neurons
A growing body of genetic research has linked the retrograde pathway to diseases of the neuronal system,
including Charcot-Marie-Tooth (CMT) disease and AD.
Two speculative reasons are generally cited to explain the
particular importance of the retrograde pathway in neurons: Neurons are large, polarized cells and the roles of the
retrograde pathway may be especially critical for maintaining the proper distributions of cell surface molecules and
signaling factors. Second, neurons are long-lived, terminally differentiated cells, and the retrograde pathway may
serve to protect against the generation and/or accumulation of toxic metabolites that lead to neuron dysfunction
and/or degeneration.
Retrograde Sorting in Development
Intercellular communication is vital for the dynamic events
by which a single cell grows, divides, and transforms into
a multi-cellular organism. Wnt proteins constitute a family of highly conserved, secreted signaling factors that
play important roles in establishing positional cues and
cell fate decisions during development. Post-translational
modifications are essential for Wnt protein activity; they
are glycosylated and lipidated in the early secretory pathway (30) and, probably because of these modifications,
release of Wnt from the cell requires an integral membrane protein called Wntless (Wls) (31–35). At steady
state, Wls localizes predominantly to the Golgi apparatus, with lesser amounts detected in the plasma membrane and endosomes, suggesting that it traffics between
these compartments. Wnt signaling during embryogenesis in fly (Drosophila melanogaster ) (31,32,34), nematode
(Caenorhabditis elegans) (34–36) and frog (Xenopus tropicalis) (36) is deficient in animals with mutations in retromer
subunits. In retromer mutants, Wnt proteins are produced
in the proper amounts and are properly modified, but
they fail to be efficiently secreted (31–35). The role of
retromer, an endosomal retrograde sorting factor, was
puzzling until the discovery that Wls is unstable in these
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Two central, functionally related components of the retrograde pathway have been implicated in neurological
disease: Rab7 and retromer. In line with the general roles
of Rab GTPases in regulating membrane and organelle trafficking, Rab7 orchestrates microtubule-dependent endosome motility and organelle tethering and fusion reactions in the late endo-lysosomal system (37). Mutations
in Rab7 that lead to dysregulation of its GTPase cycle
result in damage to sensory and motor neurons and are
responsible for hereditary Charcot-Marie-Tooth Type 2B
(CMT2B) disease (38). Although how the physiology and
pathology associated with Rab7 in CMT2B are not understood, in molecular terms the mutations increase the
abundance of GTP-bound Rab7 (39), thereby promoting
Rab7 signaling. Rab7 serves as a membrane receptor
for recruiting the retromer Vps26/29/35 sub-complex to
the endosome (40,41), so CMT2B mutations might affect
the composition and function of the endosome through
enhanced retromer activities. Significantly, retromer was
recently shown to mediate endosome recruitment of
the ‘WASH complex’, a multi-protein complex that regulates actin dynamics on the endosome and is critical
for retromer-mediated sorting (42–45). Mutations in the
gene encoding a component of the WASH complex,
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Strumpellin (44,45), result in hereditary spastic paraplegia
(HSP) (46), a disease with similar pathological features to
CMT. These similarities raise the possibility that these two
diseases may be functionally linked to a common process
through retromer. The molecular function of Strumpellin is
unknown; however, the complex that contains it appears
to be required for the F actin-dependent scission of tubules
that are decorated by retromer (42–45). Future studies will
need to address how the specific functions of retromer,
Rab7, and the WASH complex contribute to retrograde
sorting and how perturbations to their functional cycles
contribute to disease.
Alzheimer’s disease
Amyloid precursor protein, APP, is a type 1 integral membrane protein that is the precursor to amyloid β peptide
(Aβ), the predominant constituent of the amyloid plaques
that are the pathological hallmark of AD. APP localizes
predominantly to the cell surface of neurons in the brain,
but substantial pools are also detected in the TGN and
endosomes, suggesting that it cycles between these cellular locations (47). Three proteolytic activities process
APP within the endomembrane system to generate a variety of products, including Aβ: α-secretase and β site APP
cleavage enzyme (BACE; also called β-secretase) cleave at
sites within the lumenal domain, resulting in shedding of
the large ectodomain from the cell, and the third protease,
γ-secretase, cleaves within the membrane spanning segment to generate Aβ and a carboxy-terminal intracellular
product. At steady state, the bulk of α-secretase activity resides on the plasma membrane, but BACE and
γ-secretase prominently localize to endosomes and the
TGN (48,49). Thus, processing of APP is spatially restricted
to different organelles, so the abundance of the different
APP processing products, including Aβ, is largely determined by the residence time of APP in the compartments
containing the processing proteases (47). There is tremendous interest in elucidating the factors that contribute to
APP trafficking, proteolytic processing and amyloid plaque
formation, and recent evidence suggests that endosomal retrograde trafficking impacts Aβ production through
sorting of APP and its processing proteases.
The first observation to implicate retrograde trafficking
in AD came from a comparison of transcript and protein
abundances in normal versus AD brain (50). This study
observed reduced amounts of the Vps35 and Vps26
retromer subunits in the regions of the brain that are
most affected by AD and the authors suggested that this
correlates with the progression of AD. The capacity of the
endosomal retrograde pathway should be reduced as a
result of the reduction in the amount of retromer, thereby
enhancing cargo retention in maturing endosomes and
this might promote Aβ production by prolonging access
of endosome-localized BACE and γ-secretase to APP.
Consistent with this proposal, several reports find that a
reduction of retromer subunits (Vps35 or Vps26) by RNAi
or gene knockout methods results in enhanced production
of Aβ (50–54). Retromer does not appear to directly
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recognize APP, but rather, a Vps10 family sorting receptor
that binds APP, SorLA (also called SorC, SorL1 and LR11),
is a retromer cargo and may function as a sorting receptor
for retrograde transport of APP (51–57). Importantly,
genetic variants in the SORLA gene that reduce its
expression have been implicated in late onset AD (52,58).
In addition to retromer-mediated sorting of APP, the Snx17
sorting nexin is also reported to export APP from the
endosome via recognition of an NPXY sorting signal in the
cytoplasmic domain of APP and loss of Snx17 results in
enhanced production of Aβ (59). As Snx17 is not a known
component of retromer, APP may be exported from the
endosome via two independent pathways (Figure 2).
In addition to the role of the retrograde pathway in trafficking of APP, other key questions regard the sorting
of APP processing enzymes. Localization of γ-secretase
subunits by cell fractionation and fluorescence microscopy
studies suggests that the enzyme localizes to the TGN at
Figure 2: Summary of factors and pathways that mediate
endosomal retrograde sorting of APP and BACE. The clathrin
vesicle adapter, AP4, sorts APP out of the TGN via vesicles
that fuse with the endosome. Retrograde export of APP is
proposed to be mediated by association with the SorLA sorting
receptor which is packaged by retromer into tubules that return
APP to the TGN. The Snx17 sorting nexin is also reported to
directly recognize APP and confer retrograde sorting, possibly
via a retromer-independent route. The APP processing protease,
BACE, is maintained in the endosome at steady state by cycling
between the endosome and the plasma membrane, and the
endosome and the TGN. Retrograde sorting of BACE to the TGN
depends on the GGA clathrin adapter proteins and the Snx6
sorting nexin.
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Physiological Functions of the Retrograde Pathway
steady state (49), but little is known about the trafficking
pathways and signals that control its localization. BACE is
proposed to reside predominantly in the endosome (47),
though a substantial proportion is also detected in the
TGN and a lesser amount on the plasma membrane,
suggesting that it, like APP, cycles between these compartments (47). Two sorting devices, retromer and GGA
(Golgi-localizing, gamma-adaptin ear homology domain,
ADP-ribosylation factor-binding) proteins, have been implicated in controlling endosome residence of BACE. Loss
of GGA adapter function results in enhanced recycling of
BACE to the plasma membrane, and appears to diminish
TGN localization, suggesting that GGA promotes sorting of
BACE into the retrograde pathway (60,61). The retromer
subunit, Snx6, has been identified as a BACE-interacting
protein, so together, these observations suggest that GGA
and retromer co-operate to deliver BACE to the TGN (62).
The role of retromer in sorting of both APP and BACE suggests that retromer-mediated sorting may not minimize
colocalization of APP and BACE, as currently thought (47).
Rather, loss of retromer sorting may enhance Aβ production by increasing the amounts of APP and BACE in the
endo-lysosomal system. A summary of APP and BACE retrograde trafficking routes and sorting factors is presented
in Figure 2.
Current data clearly suggest that perturbations to the
endosomal retrograde sorting pathway promote the
production of Aβ. From a trafficking perspective, however,
it is far from clear how retrograde sorting devices protect
against AD. Although there is general consensus in the AD
literature that the endosome is the most relevant site of
Aβ production, solid evidence also supports the TGN as a
major site of Aβ production as well. For example, the AP4
clathrin adapter complex was recently shown to mediate
sorting of APP out of the TGN (Figure 2), and in the
absence of its function, either by RNAi-mediated depletion
of AP4, or better, by the introduction of mutations in APP
that ablate the AP4 sorting signal, APP accumulates in
the TGN and Aβ production is enhanced (63). Sources
of ambiguity regarding the contributions of particular
sorting factors in Aβ production include the commonly
employed RNAi and gene knockout approaches that
have been used for assessing the contributions of
retromer and Vps10 family receptors to Aβ production. The
loss of these ‘housekeeping’ factors affects intracellular
compartmentalization and organelle function so broadly
that at this stage it is difficult, if not impossible, to parse
the specific contributions of a particular sorting factor.
Moreover, the diverse cultured cell lines used, and wide
spectrum of efficiencies of RNAi-mediated knock-downs
documented in the published literature pose additional
challenges for comparing data from different research
groups. Clearly, better approaches are required to test and
refine current models. The identification of cargo sorting
signals and construction of loss-of-sorting point mutants
in APP and the APP processing enzymes are especially
important as it will allow more precise determinations of
steady-state localization and trafficking kinetics in cells
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where the secretory and endo-lysosomal pathways are
otherwise intact. The recent discovery of an integral
membrane protein, Gamma-secretase activating protein
(GSAP), that associates with γ-secretase and APP and
promotes Aβ production may provide an important link
for understanding how γ-secretase is directed to APP
and help to clarify the site(s) of Aβ production (64). So
far, little is known regarding the basic cell biology of
GSAP, including its steady-state intracellular localization,
sorting determinants, and where it encounters and
promotes processing of APP. The recent discovery of
small molecules that can effectively modulate retrograde
trafficking (65) established a proof of principle that
small molecules can effectively modulate cargo-specific
retrograde trafficking, raising the promise for therapeutic
intervention of trafficking pathways that contribute to AD.
Acknowledgments
Research in my laboratory is supported by grants from the US National
Institutes of Health, the American Heart Association, and the National
Science Council of Taiwan.
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