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HYPOTHESIS
Please cite this article as:
Richard N. Re, Does intracrine amplification provide a unifying principle for
the progression of common neurodegenerative disorders?
Hypothesis 2015, 13(1): e2, doi:10.5779/hypothesis.v13i1.413
1/5
Scientific Director, Ochsner Clinic Foundation
New Orleans, Lousiana, United States
Received: 2014/09/04; Accepted: 2014/10/06;
Posted online: 2015/05/26
*Correspondence:
[email protected]
© 2015 Richard N. Re. This is an Open Access article
distributed by Hypothesis under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits
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medium, provided the original work is properly cited.
kind of action is strong and the intracrine
primitive intracrine mechanism: proteins
traffic from cell to cell, cause disease, and
Does intracrine amplification provide a unifying
principle for the progression of common
neurodegenerative disorders?
Richard N. Re*
associated with these pathogenic proteins
subsequent induction of misfolding and
and that principles of intracrine biology—
pathology in those cells. This likely occurs
homeodomain
and in particular the intracellular amplifica-
in Alzheimer's disease (AD), Parkinson's
provide a clear example. Intracrines can, then re-capitulate themselves to affect
proteins, such as hormones and growth
factors, can act within their cells of synthesis or after secretion and internalization
by target cells. These factors are called
intracrines; aspects of their biology have
been defined. The actions of these factors
are mirrored in the cell-to-cell transmission
of prions and prion-like proteins in common
neurodegenerative
disorders
such
as
Alzheimer's disease. This suggests the
possibility that intracrine-like functionality is
Illustration by Eloïse Kremer
factors
tion of intracrines—can point to therapeutic
disease (PD), amyotrophic lateral sclerosis
as in angiogenesis, interact in the intra- other cells. Mechanisms of cell trafficking
strategies for the treatment of these diseas-
(ALS), tauopathies, chronic traumatic
cellular space to form intracellular regula- employed by intracrines have been
es. Here, possible modes of amplification
encephalopathy (CTE), and other NDDs. tory networks. Intracrines traffic between
of prion-like particles in neurodegenerative These diseases result from the trafficking
ABSTRACT Many extracellular signaling
transcription
cells following secretion and uptake by
proposed to be the operative modes of
trafficking for misfolded peptides as well.
disorders are explored.
of disordered proteins, and, in their inher- target cells, but also via trafficking in
Exosomes are released at synapses and
INTRODUCTION The pathogenesis of
ited forms, also from the cell-autonomous
exosomes and possibly trafficking via
exosomal trafficking of misfolded pro-
production of mutant proteins susceptible
nanotubes2,3,4.
teins complements, or even substitutes
transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob
to misfolding .
1
There are parallels between the actions
disease, kuru, scrapie, and bovine spongi- In recent years, considerable evidence
of intracrines and proteins involved in
form encephalopathy (mad cow disease)
has been developed to show that many
neurodegenerative disease; both involve
was defined by Prusiner who demon- extracellular signaling proteins can act
protein trafficking between cells and the
strated that misfolded prion proteins could
within their cells of synthesis or in target
establishment of an altered state in tar-
traffic between cells and induce mis- cells after secretion and internalization by
get cells with subsequent propagation.
folding in normal prion proteins in target
target cells. These factors are called intra- In the case of physiological intracrine
cells. As he predicted, other misfolded
crines; aspects of their biology have been
protein
defined
neurodegenerative
disorders
2,3,4
action, this process generally results in
. Many intracrines generate in- altered hormonal responsiveness or dif-
(NDDs)—which, unlike TSEs, are not
tracellular feed-forward loops that result
naturally
in target cells being placed in altered (dif- neuropeptides, it results in toxicity. These
infectious—involve
trafficking
of abnormal proteins between cells with
ferentiated) states. The evidence for this
ferentiation. In the case of the misfolded
neurodegenative disorders display a
HYPOTHESIS
for, the secretion of misfolded peptides
and/or their release from extracellular
plaques or dying cells. The trafficking
of misfolded proteins in nanotubes has
been suggested. So there are commonalities between intracrine action and the
actions of misfolded neural proteins. A
frequent feature of intracrine networks
which potentially informs the understanding of TSEs, and therefore potentially of
other NDDs, is the notion that intracrine
systems often are self-sustaining through
Vol.13, No.1 | 2015 | hypothesisjournal.com
HYPOTHESIS
Protein amplification in neurodegenerative disorders
2/5
Re
the mechanism of feed-forward regulato-
internalization by target cells, up-regula-
as a paradigm for intracrine-like action
Copper up-regulates PrPc synthesis6.
produced by abeta protein requires the
ry loops. This implies an active amplifica-
tionofintracrineproteinintargetcells,action
in neurodegeneration because they are
PrPc is found in the nucleus and could
presence of both PrPc and the micro-
tion step, which, if present in NDD, could
within target cells) are observed in the
transmissible not only between cells but
serve to buffer copper there. Were a
tubule-associated protein tau (which
provide a therapeutic target. Similarities
actions of prion-like proteins in the neu-
between organisms. That is, they are in-
significant amount of the normal prion
forms intracellular tangles that correlate
between normal and abnormal intra-
rodegenerative
mentioned
fectious (e.g., mad cow disease). Here,
protein to be replaced by scrapie prion,
with disease severity in AD) 5,6,7. Copper
crine and prion biology, including the
above. The differences are that in the
the hypothesis is applied more widely
copper buffering would be reduced and
up-regulates the synthesis of both PrPc
potential physiologic intracrine function-
neurodegenerative diseases, the pri-
to the other common neurodegenerative
PrP synthesis increased. Because it
and APP suggesting that disordered
ing of normal forms of NDD-associated
mary trafficking protein is a misfolded
disorders, which have not been shown
appears that newly synthesized PrPc is
copper handling could lead to amplifi-
proteins, have been reviewed else-
form of a normal cellular protein rather
to be infectious, and the implication of
the preferred substrate for conversion
cation of APP synthesis and secondarily
where5. From this, comes the general
than a normal intracrine, and rather than
the hypothesis that amplification is char-
to PrPsc by the abnormal scrapie prion,
to increased abeta protein synthesis5.
notion that some normal homologues of
producing a physiologic effect in target
acteristic of these disorders is similarly
this would increase the cellular load of
Abeta1-40 can in turn up-regulate tau7.
pathological prions at times act as intra-
cells, the misfolded protein produces a
widely applied to neurodegenerative
abnormal prion
disorders
c
1,5,6
. Toxicity, and traffick- The requirement for PrPc in abeta protein
crines and employ feed-forward loops
pathological effect. Nonetheless, the ba-
disorders. Moreover, possible mechan-
ing of PrP
(amplification). Once prion transforma-
sics of the processes are similar and this
isms of amplification of the relevant pro-
cells,
tion occurs, this intracrine functionality is
suggests that focusing on common in-
teins in these disorders are proposed. To
increased synthesis of PrPc in scrapie
mode of copper influx and trafficking in
coopted, or aberrant intracrine function-
tracrine functionality could lead to a new
do this, the nature of TSEs is briefly re-
infected neurons (as opposed to Peyer’s
neurons, in addition to any role played
ality is developed, to spread pathology in
understanding of not only the nature of
viewed and the illustrated principles then
patch
been
by direct PrPc binding of abeta protein.
the nervous system.
TSEs but also of other common neuro-
applied more widely. Potential intracrine
detected, no detailed exploration of this
APP and abeta protein bind copper, and
HYPOTHESIS It is proposed that the
degenerative disorders. In particular, the
pathways in selected neurodegenerative
issue has been undertaken and inter-
their arrival via exosomes in target cells
hypothesis that these neuroencepha-
disorders are proposed.
pretation of the available data is compli-
could disrupt copper regulation in those
lopathies are intracrine in nature implies
SUPPORTING INFORMATION It is pro- cated by neuronal cell loss during
cells, enhancing disease propagation.
posed that the up-regulation, by any of
In amyotrophic lateral sclerosis, two mis-
neurodegenerative
diseases
recently
suggested to develop from the propagation of transmissible proteins between brain cells—diseases such as
Creutzfeldt-Jakob disease and other
transmissible spongiform encephalopathies, Alzheimer’s disease, Parkinson’s
disease, amyotrophic lateral sclerosis
(Lou Gehrig disease), and chronic traumatic encephalopathy—result from distorted intracrine physiology. That is, the
same actions characteristic of intracrines
(function within the cell, trafficking by
one means or another to adjacent cells,
that transmissible prion-like protein upregulation (amplification) occurs in target
cells. If the amplification of intracrines in
target cells is mirrored in the amplification of prion-like proteins in target cells as
is hypothesized here, this would present
a new therapeutic target. The notion that
intracrine biology plays a role in these
common neurodegenerative disorders
has been suggested elsewhere in the
case of the transmissible spongiform encephalopathies (TSEs) 5. The TSEs serve
a variety of mechanisms, of the normal
forms of the common NDD-associated
proteins is essential for disease progression. In the case of the TSEs, one can
note that synthesis of normal cellular
prion protein PrPc is essential to the prop-
sc
via endosomes to nearby
could
then
lymphocytes)
result.
has
Although
not
disease5. Also, it is possible that upregulation of PrPc synthesis need only be
required in the initial phase of infection
so as to produce sufficient abnormal
prion
protein
to
permit
ongoing
production with a more normal rate of
PrPc production.
in vitro neurotoxicity could result from
the protein's role in providing an efficient
folded proteins have been associated
with disease: copper-zinc superoxide
dismutase 1 (SOD1) and TDP431,10-13. For
brevity, TDP43 will be discussed here.
TDP43 is a multifunctional DNA and
RNA binding protein that is involved in
agation of abnormal scrapie prion PrPsc 1-9.
Similarly, the progression of AD requires
RNA splicing. Interestingly, it controls
Suppression of PrPc synthesis at any
the production of amyloid precursor
its own synthesis by binding its own
point stops disease progression . PrP ,
protein (APP), which is cleaved to form
mRNA. Decreased TDP43 protein leads
but not PrPsc, binds and transports cop-
the toxic extracellular plaque-forming
to increased translation of its message
per (as well as iron and zinc) into cells.
abeta protein, while in vitro neurotoxicity
and increased synthesis of the protein;
HYPOTHESIS
Vol.13, No.1 | 2015 | hypothesisjournal.com
8
c
HYPOTHESIS
Protein amplification in neurodegenerative disorders
3/5
Re
that is, it leads to up-regulation. In ALS, copper, zinc, and iron are transported
common up-regulation of PrPc, and
other substrate proteins. Up-regulation
For example, reducing CNS copper con-
TDP43 aggregates in the cytoplasm with
APP by copper, STOX1A may represent
of substrate proteins could then lead to
centrations by dietary or other means
a near absence of TDP43 in the nucleus. participation of PrPc in the disease5,6,9. another case of interaction between the
the stochastic development of misfolded
would be expected to decrease PrPc syn-
into cells by PrPc, these data suggest
Toxicity likely results from the loss of
However, whereas PrP down-regulation
pathologies of the NDDs. Although tau
proteins which, in turn, serve as seeds for
thesis and disease progression in TSEs
TDP43-mediated regulation of cellular
by zinc (secondary to internalization of
tangles are not seen in ALS, they are
the formation of aggregates and disease
and possibly in other NDDs. Although an
propagation18,19,20.
abeta protein preparation recently has
c
mRNAs as a result of TDP43 sequestra- PrPc by zinc) may be beneficial in TSEs, prominent in the related disorder chronic
tion in cytoplasmic aggregates. Thus, if
as noted in the case of TDP43 aggre- traumatic encephalopathy (CTE) where
an abnormal TDP43 fragment is taken
gation, the effects of zinc appear to be
abeta
protein,
TDP43,
and
alpha-
up by a target cell and seeds cyto- more complex in other NDDs.
synuclein inclusions can also be found
plasmic aggregation of endogenous
in some cases17. Trauma likely produces
TDP43, then cellular TDP43 will be upregulated and the disease will progress.
It is possible that another form of amplification occurs in ALS. APP and cellular
copper are increased in ALS. There is
some indirect evidence to suggest
modest TDP43 up-regulation by copper
compounds13. Tissue iron also is increased
suggesting
impaired
APP
ferroxidase activity as may occur in AD
secondary to extracellular zinc release
from plaques12. If the increased cellular
iron in ALS does in fact result from
increased extracellular zinc (whether
through ferroxidase inhibition or some
other effect on APP iron export), this
could be important. Extracellular zinc
causes intracellular TDP43 aggregation,
thereby
TDP43
down-regulating
and
up-regulating
functional
TDP43
synthesis . This would be expected to
11
enhance production of TD43 prion-like
particles and disease spread. Because
Several NDDs, while expressing one
prominent misfolded protein, express
variable levels of others, suggesting
some commonality of regulation and/or
intracrine-like regulatory networking. One
protein commonly involved is tau, which
also appears to be the primary protein
in disorders such as progressive supranuclear palsy. Possible amplification
mechanisms for tau, in addition to upregulation by abeta1-40, are only beginning to emerge. The transcription factor
STOX1A in some circumstances can upregulate tau. STOX1A down-regulates
CNTNAP2, a member of the neurexin
family. In the hippocampus of AD
patients, STOX1A expression is upregulated, while CNTNAP2 is downregulated
14,15,16
STOX1A,
a
. Thus, in the case of
mechanism
which
a
wide-ranging
disorder,
possibly
because cytoplasmic RNA/protein stress
granules are formed after trauma to
protect the brain, and these lead to the
aggregation of the mRNAs of many
disease-related proteins. Alterations in
the amounts of these proteins could lead
to disordered homeostasis, including
disordered transitional metal homeostasis. Amplification of each factor could
then occur. For example, TDP43 RNA is
sequestered in stress granules and this
should up-regulate TDP43 gene expression. Up-regulated TDP43 interacts with
tau mRNA and, depending on the details
of this interaction and the rate at which
TDP43 is aggregated, the result could be
up-regulated tau mRNA translation.
up- Similarly, the mRNA binding protein
The hypothesis has several implications.
First, evidence of substrate protein amplification should be sought in all NDDs—
and confirmed in Parkinson's disease
where amplification has already been
reported21. Second, prevention of amplification is a disease-controlling strategy;
complete knock-down of substrate protein is unnecessary. Third, intracrinelike networks linking the regulation of
various misfolded proteins should be
sought; their interruption would be therapeutically beneficial in disease modification. These networks, usually weak and
indolent, can, as is likely in some cases
of CTE and AD, be more robust. They
are likely mediated by misfolded proteindriven regulation of transition metal
transport. Fourth, PrPc likely plays an
important role in the non-heritable forms
of many of these disorders, not only in
TSEs, by virtue of its ability to transport
copper, zinc, and iron with secondary
regulation of substrate proteins (this need
been reported to cause disease somewhat
resembling AD pathology in PrPc-/- knockout animals (while a five-fold over-expression of PrPc in transgenic animals was actually protective), and although PrPc levels
have been reported to be reduced in sporadic (but not heritable) AD frontal cortex,
PrPc expression is required for neurotoxicity
in vitro and in at least one in vivo model
suggesting a complex relationship between PrPc and AD5,22-24. Indeed, there is
evidence that at least some of the likely
pathological interaction between PrPc and
abeta protein involves the direct binding
of the two. But PrPc accounts for only about
50% of the cell binding of abeta protein
and so it is likely that other cell proteins
can at least partially substitute for it 22.
Additional research will be required to
define the role of PrPc in AD, but it must be
noted that abeta protein is the major prionlike protein involved in AD, and PrPc likely
plays only a permissive or supplemental
role5,22.
regulates tau may directly participate
HuD is sequestered in stress granules
in neurodegeneration in AD through
and this relieves the protein's suppres- not be the case in genetic forms of the
Nonetheless, it is likely that PrPc knock-
the down-regulation of CNTNAP2. Like
sion of tau synthesis. Intracrine-like reg- disorders where amplification can be
down in AD is beneficial. In ALS, PrPc
tau, up-regulation by abeta1-40 and the
ulatory networking could up-regulate
likely facilitates pathogenic zinc entry
unnecessary).
HYPOTHESIS
Vol.13, No.1 | 2015 | hypothesisjournal.com
HYPOTHESIS
Protein amplification in neurodegenerative disorders
4/5
Re
into cells and PrPc is therefore a possi-
phenotype changes and knocking down
the neurodegenerative disorders differ
Foundation, and is on the faculty of Tulane
prion infection prevents disease and reverses spon-
ble therapeutic target in that disorder as
PrPc in PrPsc infected mice produces
from those involved in the normal physi-
University School of Medicine.
giosis. Science.2003;302:871-4.
REFERENCES
9 Watt NT, Taylor DR, Kerrigan TL, Griffiths HH,
well as in TSEs . Several drugs such as
definite therapeutic benefit . The thrust
ologic up-regulation of the respective
glimepiride, all-trans-retinoic acid, aste-
of all these observations is the sugges-
proteins. Therefore, these neurodegen-
mizole, and tacrolimis have been shown
tion that because of interactions be-
erative disorders properly should be con-
to lower cell surface PrPc expression at
tween prion-like proteins, it is possible
sidered intracrine-like to distinguish them
5,11
8,25
one concentration or another; they could
c
that certain interventions such as PrP
from physiological intracrine systems.
serve as prototypes for the development
knock-down or metal chelation could
They utilize an aberrant intracrine physi-
of common therapies for NDDs and in
prove beneficial in more than one dis-
ology. This has a variety of implications
particular for TSEs, ALS, and CTE 25-27.
ease. That is, just as physiological intra-
including potential therapeutic implica-
Glimepiride, approved for the treatment
crines can form interacting networks, so
tions. Currently, a great deal of effort is
of diabetes mellitus, may be a particularly
too may pathological prion-like proteins.
directed to devising methods for limiting
useful prototype not only in TSEs where
If so, this would present therapeutic op-
the spread of prion-like proteins between
it lowers cell surface PrPc, but also in
portunities. Finally, in addition to their
cells. The hypothesis presented here
AD, both because it lowers cell surface
established roles in the aggregation of
suggests, among other things, that
PrPc (and therefore disease-enhancing
misfolded proteins, it is argued here that
aberrant protein amplification should
PrPc pathologic effects) and because it
transition metals play important roles in
be considered a therapeutic target in all
induces shedding of PrPc into the extra-
protein amplification. Interrupting that
of these disorders. More importantly, al-
cellular space where it can bind abeta
amplification likely also is a common
though TSEs serve as the paradigm for
protein—a mechanism that has been
therapeutic strategy in these neurode-
intracrine involvement in neurodegen-
proposed to be protective in the PrPc
generative disorders. erative disorders, it is proposed here
CONCLUSION It is hypothesized here
that common intracrine mechanisms are
over-expression transgenic model mentioned above
22,23,26
. that there are clear parallels between
operative in all these neurodegenerative
diseases.H
1 Prusiner SB. A unifying role for prions in neurodegenerative diseases. Science. 2012;336:1511-3.
http://dx.doi.org/10.1126/science.1222951
2 Re RN, Cook JL. Senescence, apoptosis, and stem
cell biology: the rationale for an expanded view of
intracrine action. Am J Physiol Heart Circ Physiol
2009; 297:H893-901. Epub 2009 Jul 10.
http://dx.doi.org/10.1152/ajpheart.00414.2009
3 Re RN, Cook JL. The physiological basis of intracrine stem cell regulation. Am J Physiol Heart Circ
Physiol. 2008;295:H447-53.
http://dx.doi.org/10.1152/ajpheart.00461.2008
4 Re RN, Cook JL. An intracrine view of angiogenesis. Bioessays 2006;28:943-53.
5 Re RN. Could intracrine biology play a role in the
pathogenesis of transmissable spongiform encephalopathies, Alzheimer's disease and other neurodegenerative diseases? Am J Med Sci. 2014;347:31220. http://dx.doi.org/10.1097/MAJ.0b013e3182a28af3
6 Armendariz AD, Gonzalez M, Loguinov AV, Vulpe
Zinc, because it internalizes with PrP
physiologic intracrine action and the
without up-regulating PrP
synthesis,
pathological action of prion-like proteins.
ACKNOWLEDGEMENT This work was
could act beneficially in TSEs (but likely
At the same time, there are clear differ-
funded by the Ochsner Clinic Foundation.
not in other NDDs) by internalizing cell-
ences between normal intracrine func-
surface PrP
. Intrathecal administration
tion and the action of prion-like proteins
CONFLICTS OF INTEREST Author de- 7 Wang C, Wurtman RJ, Lee RK. Amyloid precur-
of liposomes containing PrP antisense
in neurodegenerative diseases. For ex-
or anti-PrPc siRNA also could be con-
ample, intracrine action is generally
sidered. PrPc knock-down is not likely to
physiological, whereas misfolded prion-
be harmful given the fact that transgenic
like proteins are pathological; also the
PrP
mechanisms of protein amplification in
c
c
c 5,9
c
c-/-
animals
demonstrate
minimal
CD. Gene expression profiling in chronic copper
overload reveals upregulation of Prnp and App.
Physiol Genomics. 2004;20:45-54.
clare no conflicts of interest.
sor protein and membrane phospholipids in primary
ABOUT THE AUTHOR The author is a physi-
cortical neurons increase with development, or af-
cian who conducts research on the cellular
biology of vasoactive proteins. He currently
serves as Scientific Director, Ochsner Clinic
ter exposure to nerve growth factor or Abeta(1-40).
Brain Res. 2000;865:157-67.
8 Mallucci G, Dickinson A, Linehan J, Klöhn PC,
Brandner S, Collinge J. Depleting neuronal PrP in
HYPOTHESIS
Rushworth JV, Whitehouse IJ, Hooper NM. Prion
protein facilitates uptake of zinc into neuronal cells.
Nat Commun. 2012;3:1134.
http://dx.doi.org/10.1038/ncomms2135
10 Da Cruz S, Cleveland DW. Understanding the role
of TDP-43 and FUS/TLS in ALS and beyond. Curr
Opin Neurobiol. 2011;21:904-19.
http://dx.doi.org/10.1016/j.conb.2011.05.029.
11 Caragounis A, Price KA, Soon CP, Filiz G,
Masters CL, Li QX, et al. Zinc induces depletion and
aggregation of endogenous TDP-43. Free Radic Biol
Med. 2010;48:1152-61.
http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.035
12 Duce JA, Tsatsanis A, Cater MA, James SA, Robb
E, Wikhe K, et al. Iron-export ferroxidase activity of
b-amyloid precursor protein is inhibited by zinc in
Alzheimer's disease. Cell. 2010;142:857-67.
http://dx.doi.org/10.1016/j.cell.2010.08.014
13 Parker SJ, Meyerowitz J, James JL, Liddell JR,
Nonaka T, Hasegawa M, et al. Inhibition of TDP-43
accumulation by bis(thiosemicarbazonato)-copper
complexes. PLoS One. 2012;7:e42277.
http://dx.doi.org/10.1371/journal.pone.0042277
14 van Abel D, Hölzel DR, Jain S, Lun FM, Zheng YW,
Chen EZ, et al. SFRS7-mediated splicing of tau exon 10
is directly regulated by STOX1A in glial cells. PLoS One.
2011;6:e21994.
http://dx.doi.org/10.1371/journal.pone.0021994
15 van Dijk M, van Bezu J, Poutsma A, Veerhuis R,
Rozemuller AJ, Scheper W, et al. The pre-
Vol.13, No.1 | 2015 | hypothesisjournal.com
HYPOTHESIS
Protein amplification in neurodegenerative disorders
5/5
Re
eclampsia gene STOX1 controls a conserved path-
21 Gründemann J, Schlaudraff F, Haeckel O, Liss B.
27 Karapetyan YE, Sferrazza GF, Zhou M, Ottenberg G,
way in placenta and brain upregulated in late-on-
Elevated alpha-synuclein mRNA levels in individual
Spicer T, Chase P, et al. Unique drug screening
set Alzheimer's disease. J Alzheimers Dis. 2010;19:
UV-laser-microdissected dopaminergic substantia
approach for prion diseases identifies tacrolimus
673-9.
nigra neurons in idiopathic Parkinson's disease.
and astemizole as antiprion agents. Proc Natl Acad
http://dx.doi.org/10.3233/JAD-2010-1265
Nucleic Acids Res. 2008;36:e38.
Sci U S A. 2013;110:7044-49.
16 van Abel D, Michel O, Veerhuis R, Jacobs M,
http://dx.doi.org/10.1093/nar/gkn084
http://dx.doi.org/10.1073/pnas.1303510110
van Dijk M, Oudejans CB. Direct downregulation of
22 Kudo W, Lee HP, Zou WQ, Wang X, Perry G, Zhu
CNTNAP2 by STOX1A is associated with Alzheimer's
X, et al. Cellular prion protein is essential for oligo-
disease. J Alzheimers Dis. 2012;31:793-800.
meric amyloid-b-induced neuronal cell death. Hum
http://dx.doi.org/10.3233/JAD-2012-120472
Mol Genet. 2012;21:1138-44.
17 McKee AC, Stein TD, Nowinski CJ, Stern RA,
http://dx.doi.org/10.1093/hmg/ddr542
Daneshvar DH, Alvarez VE, et al. The spectrum of
23 Rial D, Piermartiri TC, Duarte FS, Tasca CI, Walz
disease in chronic traumatic encephalopathy. Brain.
R, Prediger RD. Overexpression of cellular prion
2013;136(Pt 1): 43-64. Erratum in: Brain. 2013
protein (PrP(C)) prevents cognitive dysfunction and
Oct;136(Pt 10):e255.
apoptotic neuronal cell death induced by amyloid-
http://dx.doi.org/10.1093/brain/aws307
b (Ab1-40) administration in mice. Neuroscience.
18 Sephton CF, Cenik C, Kucukural A, Dammer EB,
2012;215:79-89.
Cenik B, Han Y, et al. Identification of neuronal RNA
http://dx.doi.org/10.1016/j.neuroscience.2012.04.034
targets of TDP-43-containing ribonucleoprotein
24 Whitehouse IJ, Miners JS, Glennon EB, Kehoe
complexes. J Biol Chem. 2011; 286:1204-15.
PG, Love S, Kellett KA, Hooper NM. Prion protein
http://dx.doi.org/10.1074/jbc.M110.190884
is decreased in Alzheimer's brain and inversely cor-
19 Parker SJ, Meyerowitz J, James JL, Liddell JR,
relates with BACE1 activity, amyloid-b levels and
Crouch PJ, Kanninen KM, White AR. Endogenous
Braak stage. PLoS One. 2013;8:e59554.
TDP-43 localized to stress granules can subse-
http://dx.doi.org/10.1371/journal.pone.0059554
quently form protein aggregates. Neurochem Int.
25 Rybner C, Hillion J, Sahraoui T, Lanotte M, Botti
2012;60:415-24.
J. All-trans retinoic acid down-regulates prion pro-
http://dx.doi.org/10.1016/j.neuint.2012.01.019
tein expression independently of granulocyte matu-
20 Atlas R, Behar L, Sapoznik S, Ginzburg I.
ration. Leukemia 2002;16:940-8.
Dynamic association with polysomes during P19
26 Bate C, Tayebi M, Diomede L, Salmona M,
neuronal differentiation and an untranslated-region-
Williams A. Glimepiride reduces the expression
dependent translation regulation of the tau mRNA by
of PrPc, prevents PrPsc formation and protects
the tau mRNA-associated proteins IMP1, HuD, and
against prion mediated neurotoxicity in cell lines.
G3BP1. Neurosci Res. 2007;85:173-83.
PLoS One. 2009;4:e8221.
http://dx.doi.org/10.1371/journal.pone.0008221
HYPOTHESIS
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