Protein aggregation: Difference between revisions
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==Introduction== |
==Introduction== |
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After synthesis, proteins typically fold into a particular three-dimensional conformation: their native state. |
After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state.<ref>{{Cite journal|last=Brüning|first=Ansgar|last2=Jückstock|first2=Julia|date=2015-01-01|title=Misfolded proteins: from little villains to little helpers in the fight against cancer|url=http://journal.frontiersin.org/Article/10.3389/fonc.2015.00047/abstract|journal=Cancer Molecular Targets and Therapeutics|volume=5|pages=47|doi=10.3389/fonc.2015.00047|pmc=4338749|pmid=25759792}}</ref> They are only functional in their native state. This folding process is driven by the [[hydrophobic effect]]: a tendency for hydrophobic (i.e., “oil-ly”) portions of the protein to shield itself from the hydrophilic interior of the cell by burying into the interior of the protein. Thus, the exterior of a protein is typically hydrophilic, whereas the interior is typically hydrophobic. |
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The protein is stabilized by [[Covalent bond|covalent]] and noncovalent interactions. Covalent interactions involve covalent bonds such as the disulfide bridge that forms between two cysteine residues. It plays an important role in stabilizing a protein's tertiary and quarternary structure. The noncovalent interactions include ionic interactions and weak van der waals interactions. Ionic interactions form between an anion and a cation and form salt bridges that help stabilize the protein. Van der waals interactions include nonpolar and polar interactions. The nonpolar interactions refer to the London dispersion forces between the hydrophobic parts of the amino acids. Although they are weak, they are very abundant so they have a large affect on the protein's stability. Polar interactions include hydrogen bonding and dipole-dipole interactions. These play an important role in a protein's secondary structure, such as forming an [[alpha helix]] or a beta sheet. Electrostatic interactions between amino acid residues in a specific protein are very important in that protein's final structure. When there are changes in the electrostatic interactions, as may happen with a change in the amino acid sequence, the protein is susceptible to misfolding or unfolding. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded/misfolded protein may aggregate.<ref name="Gething-1992">{{Cite journal | last1 = Gething | first1 = MJ. | last2 = Sambrook | first2 = J. | title = Protein folding in the cell | journal = Nature | volume = 355 | issue = 6355 | pages = 33–45 |date=January 1992 | doi = 10.1038/355033a0 |pmid = 1731198}}</ref><ref name="Roberts-2007">{{Cite journal | last1 = Roberts | first1 = CJ. | title = Non-native protein aggregation kinetics | journal = Biotechnol Bioeng | volume = 98 | issue = 5 | pages = 927–38 |date=December 2007 | doi = 10.1002/bit.21627 |pmid = 17705294}}</ref> In this process, exposed hydrophobic portions of the protein may interact with the exposed hydrophobic patches of other proteins, spontaneously leading to protein aggregation. There are three main types of protein aggregates that may form: amorphous aggregates, [[oligomer]]s, and [[amyloid]] fibrils.<ref>{{Cite book|title=Lehninger Principles of Biochemistry|last=Cox|first=David L.|last2=Nelson|first2=Michael M.|publisher=W.H. Freeman|year=2013|isbn=978-1-4292-3414-6|location=New York|pages=143}}</ref> |
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==Causes== |
==Causes== |
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Protein aggregation can occur due to a variety of causes. There are four classes that these causes can be categorized into, which are detailed below. |
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Protein aggregation can occur due to a variety of causes. Individuals may have mutations that encode for proteins that are particularly sensitive to misfolding and aggregation. Alternatively, disruption of the pathways to refold proteins (chaperones) or to degrade misfolded proteins (the ubiquitin-proteasome pathway) may lead to protein aggregation. As many of the diseases associated with protein aggregation increase in frequency with age, it seems that cells lose the ability to clear misfolded proteins and aggregates over time. |
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Several new studies suggest that protein aggregation is a second line of the cellular reaction to an imbalanced protein homeostasis rather than a harmful, random process.<ref>http://www.nature.com/nrm/journal/v11/n11/full/nrm2993.html</ref> |
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=== Mutations === |
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A groundbreaking study<ref>{{cite journal | pmc = 2746971 | pmid=18756251 | doi=10.1038/nature07195 | volume=454 | title=Misfolded proteins partition between two distinct quality control compartments | date=August 2008 | author=Kaganovich D, Kopito R, Frydman J | journal=Nature | pages=1088–95}}</ref> showed that sequestration of misfolded, aggregation-prone proteins into inclusion sites is an active organized cellular process, that depends on quality control components, such as HSPs and co-chaperones. |
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Mutations that occur in the DNA sequence may affect the amino acid sequence of the protein. Often times, a different amino acid sequence may change the electrostatic interactions between the side chains that affect the folding of the protein. This can lead to exposed hydrophobic regions of the protein that aggregate with the same misfolded/unfolded protein or a different protein. |
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Moreover, it was [[JUNQ and IPOD|shown]] that eukaryotic cells have the ability to sort misfolded proteins in to two quality control compartments: 1. The [[JUNQ and IPOD|JUNQ]] (JUxta Nuclear Quality control compartment). 2. The [[JUNQ and IPOD|IPOD]] (Insoluble Protein Deposit). The partition into two quality control compartments is due to the different handling and processing of the different kinds of misfolded aggregative proteins: The IPOD serves as a sequestration site for non-ubiquitinated terminally aggregated proteins, such as the huntingtin protein. Under stress conditions, such as heat, when the cellular quality control machinery is saturated, ubiquitinated proteins are sorted to the JUNQ compartment, where they are eventually degraded. |
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Thus, aggregation is a regulated, controlled process. |
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In addition to mutations in the affected proteins themselves, protein aggregation could also be caused indirectly through mutations in proteins in regulatory pathways such as the refolding pathway (molecular chaperones) or the ubiquitin-proteasome pathway (ubiquitin ligases).<ref>{{Cite journal|last=Berke|first=Sarah J Shoesmith|last2=Paulson|first2=Henry L|date=2003-06-01|title=Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration|url=http://www.sciencedirect.com/science/article/pii/S0959437X03000534|journal=Current Opinion in Genetics & Development|volume=13|issue=3|pages=253–261|doi=10.1016/S0959-437X(03)00053-4}}</ref> [[Chaperone (protein)|Chaperones]] help with protein refolding by providing a safe environment for the protein to fold. Ubiquitin ligases target proteins for degradation through ubiquitin modification. |
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=== Problems with Protein Synthesis === |
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Protein aggregation can be caused by problems that occur during [[Transcription (genetics)|transcription]] or [[Translation (biology)|translation]]. During transcription, DNA is copied into mRNA through a detailed process in which the double-stranded helix is opened up and RNA Polymerase adds complementary ribonucleic acids to form a strand of pre-mRNA that undergoes RNA processing to form mRNA.<ref name=":0">{{Cite book|title=Molecular Biology|last=Weaver|first=Robert F.|publisher=McGraw-Hill|year=2012|isbn=978-0-07-352532-7|location=New York|pages=122-156, 523-600}}</ref> During this process, issues may arise that could cause an incorrect mRNA strand to form. If the incorrect mRNA encodes for a different amino acid sequence, this could cause the protein to misfold, leading to protein aggregation. During translation, ribosomes and tRNA help translate the mRNA sequence into an amino acid sequence.<ref name=":0" /> Similarly, if problems arise during this step, such as if the tRNA brings an incorrect amino acid, this would also lead to an incorrect amino acid sequence and can cause the protein to misfold. |
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=== Environmental Stresses === |
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Environmental stresses such as extreme temperatures and pH or oxidative stress can also lead to protein aggregation.<ref name=":1">{{Cite journal|last=Tyedmers|first=Jens|last2=Mogk|first2=Axel|last3=Bukau|first3=Bernd|title=Cellular strategies for controlling protein aggregation|url=http://www.nature.com/doifinder/10.1038/nrm2993|journal=Nature Reviews Molecular Cell Biology|volume=11|issue=11|pages=777–788|doi=10.1038/nrm2993}}</ref> |
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Extreme temperatures and pH can can affect protein folding. Extreme temperatures can weaken and destabilize the electrostatic attractions between the amino acid residues. This can cause the protein to unfold and aggregate. Similarly, pH also affect protein folding by changing the protonation state of the amino acids. This may decrease their electrostatic interactions, leading to less stable interactions and protein unfolding. |
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Oxidative stress can be caused by radicals such as reactive oxygen species (ROS). These unstable radicals can attack the side chains of the amino acid residues, causing protein modifications such as replacing the side chains with carbonyl groups. This, in turn, affects the electrostatic interactions that hold the protein together correctly and may cause the protein to unfold or misfold.<ref name=":1" /> |
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=== Ageing === |
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Cells have mechanisms that can refold or degrade protein aggregates. However, as cells age, these control mechanisms are weakened and the cell is less able to resolve the aggregates.<ref name=":1" /> |
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== Protein aggregation and Aging == |
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The |
The |
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hypothesis that protein aggregation is a causative process in aging is testable |
hypothesis that protein aggregation is a causative process in aging is testable |
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has been tested and confirmed in mammals as reducing the activity of the IGF-1 |
has been tested and confirmed in mammals as reducing the activity of the IGF-1 |
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signaling pathway protected Alzheimer's model mice from the behavioral and |
signaling pathway protected Alzheimer's model mice from the behavioral and |
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biochemical impairments associated with the disease.<ref>{{Cite journal| |
biochemical impairments associated with the disease.<ref>{{Cite journal|last=|first=|date=2002|title=The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditiselegans|url=http://www.pnas.org/content/99/16/10417.short|journal=PNAS|volume=99|pages=10417–10422|doi=10.1073/pnas.152161099|accessdate=|author=}}</ref> |
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== Protein Aggregate Localization == |
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Several studies have shown that cellular responses that occur because of protein aggregation are well-regulated and organized cellular processes. One example of this is the specific localization areas in different cells that the protein aggregates go to. |
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=== Yeast === |
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Protein aggregates can be localized at the Juxtanuclear quality-control compartment (JUNQ) which is near the nuclear membrane or at the Insoluble Protein deposit (IPOD) near the vacuole in yeast cells.<ref name=":1" /> Protein aggregates localize at JUNQ when they are targeted for degradation by ubiquitination. The aggregated and insoluble proteins localize at IPOD as a more permanent deposition. They do not get degraded at IPOD. These two pathways work together in that the proteins tend to come to the IPOD when the proteasome pathway is being overworked.<ref name=":1" /> |
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=== Mammalian cells === |
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In mammalian cells, these protein aggregates are termed "aggresomes" and they are only formed when the cell is diseased. The aggresomes localize at the microtubule organizing center (MTOC). Ubiquitin and HDAC6 assist with this localization. the E3 ubiquitin ligase is able to recognize misfolded proteins and ubiquinate them. Then, HDAC6 binds to the ubiquitin and the motor protein [[dynein]] to bring the marked aggresome to the MTOC.<ref name=":1" /> |
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==Toxicity== |
==Toxicity== |
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Revision as of 21:34, 19 May 2016
Protein aggregation is a biological phenomenon in which mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly.[1][2] These protein aggregates are often toxic; protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.[3][4]
Introduction
After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state.[5] They are only functional in their native state. This folding process is driven by the hydrophobic effect: a tendency for hydrophobic (i.e., “oil-ly”) portions of the protein to shield itself from the hydrophilic interior of the cell by burying into the interior of the protein. Thus, the exterior of a protein is typically hydrophilic, whereas the interior is typically hydrophobic.
The protein is stabilized by covalent and noncovalent interactions. Covalent interactions involve covalent bonds such as the disulfide bridge that forms between two cysteine residues. It plays an important role in stabilizing a protein's tertiary and quarternary structure. The noncovalent interactions include ionic interactions and weak van der waals interactions. Ionic interactions form between an anion and a cation and form salt bridges that help stabilize the protein. Van der waals interactions include nonpolar and polar interactions. The nonpolar interactions refer to the London dispersion forces between the hydrophobic parts of the amino acids. Although they are weak, they are very abundant so they have a large affect on the protein's stability. Polar interactions include hydrogen bonding and dipole-dipole interactions. These play an important role in a protein's secondary structure, such as forming an alpha helix or a beta sheet. Electrostatic interactions between amino acid residues in a specific protein are very important in that protein's final structure. When there are changes in the electrostatic interactions, as may happen with a change in the amino acid sequence, the protein is susceptible to misfolding or unfolding. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded/misfolded protein may aggregate.[6][7] In this process, exposed hydrophobic portions of the protein may interact with the exposed hydrophobic patches of other proteins, spontaneously leading to protein aggregation. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils.[8]
Causes
Protein aggregation can occur due to a variety of causes. There are four classes that these causes can be categorized into, which are detailed below.
Mutations
Mutations that occur in the DNA sequence may affect the amino acid sequence of the protein. Often times, a different amino acid sequence may change the electrostatic interactions between the side chains that affect the folding of the protein. This can lead to exposed hydrophobic regions of the protein that aggregate with the same misfolded/unfolded protein or a different protein.
In addition to mutations in the affected proteins themselves, protein aggregation could also be caused indirectly through mutations in proteins in regulatory pathways such as the refolding pathway (molecular chaperones) or the ubiquitin-proteasome pathway (ubiquitin ligases).[9] Chaperones help with protein refolding by providing a safe environment for the protein to fold. Ubiquitin ligases target proteins for degradation through ubiquitin modification.
Problems with Protein Synthesis
Protein aggregation can be caused by problems that occur during transcription or translation. During transcription, DNA is copied into mRNA through a detailed process in which the double-stranded helix is opened up and RNA Polymerase adds complementary ribonucleic acids to form a strand of pre-mRNA that undergoes RNA processing to form mRNA.[10] During this process, issues may arise that could cause an incorrect mRNA strand to form. If the incorrect mRNA encodes for a different amino acid sequence, this could cause the protein to misfold, leading to protein aggregation. During translation, ribosomes and tRNA help translate the mRNA sequence into an amino acid sequence.[10] Similarly, if problems arise during this step, such as if the tRNA brings an incorrect amino acid, this would also lead to an incorrect amino acid sequence and can cause the protein to misfold.
Environmental Stresses
Environmental stresses such as extreme temperatures and pH or oxidative stress can also lead to protein aggregation.[11]
Extreme temperatures and pH can can affect protein folding. Extreme temperatures can weaken and destabilize the electrostatic attractions between the amino acid residues. This can cause the protein to unfold and aggregate. Similarly, pH also affect protein folding by changing the protonation state of the amino acids. This may decrease their electrostatic interactions, leading to less stable interactions and protein unfolding.
Oxidative stress can be caused by radicals such as reactive oxygen species (ROS). These unstable radicals can attack the side chains of the amino acid residues, causing protein modifications such as replacing the side chains with carbonyl groups. This, in turn, affects the electrostatic interactions that hold the protein together correctly and may cause the protein to unfold or misfold.[11]
Ageing
Cells have mechanisms that can refold or degrade protein aggregates. However, as cells age, these control mechanisms are weakened and the cell is less able to resolve the aggregates.[11]
The hypothesis that protein aggregation is a causative process in aging is testable now since some models of delayed aging are in hand. If the development of protein aggregates was an aging independent process, slowing down aging will show no effect on the rate of proteotoxicity over time. However, if aging is associated with decline in the activity of protective mechanisms against proteotoxicity, the slow aging models would show reduced aggregation and proteotoxicity. To address this problem several toxicity assays have been done in C. elegans. These studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer's model mice from the behavioral and biochemical impairments associated with the disease.[12]
Protein Aggregate Localization
Several studies have shown that cellular responses that occur because of protein aggregation are well-regulated and organized cellular processes. One example of this is the specific localization areas in different cells that the protein aggregates go to.
Yeast
Protein aggregates can be localized at the Juxtanuclear quality-control compartment (JUNQ) which is near the nuclear membrane or at the Insoluble Protein deposit (IPOD) near the vacuole in yeast cells.[11] Protein aggregates localize at JUNQ when they are targeted for degradation by ubiquitination. The aggregated and insoluble proteins localize at IPOD as a more permanent deposition. They do not get degraded at IPOD. These two pathways work together in that the proteins tend to come to the IPOD when the proteasome pathway is being overworked.[11]
Mammalian cells
In mammalian cells, these protein aggregates are termed "aggresomes" and they are only formed when the cell is diseased. The aggresomes localize at the microtubule organizing center (MTOC). Ubiquitin and HDAC6 assist with this localization. the E3 ubiquitin ligase is able to recognize misfolded proteins and ubiquinate them. Then, HDAC6 binds to the ubiquitin and the motor protein dynein to bring the marked aggresome to the MTOC.[11]
Toxicity
Although it has been thought that the mature protein aggregates themselves are toxic, recent evidence suggests that it is in fact that immature protein aggregates are most toxic.[13][14] The hydrophobic patches of these aggregates can interact with other components of the cell and damage them. One hypothesis about how protein aggregates damage cells is through disruption of cell membranes. It is known that protein aggregates in vitro can destabilize artificial phospholipid bilayers, leading to permeabilization of the membrane.
See also
External links
References
- ^ Aguzzi, A.; O'Connor, T. (March 2010). "Protein aggregation diseases: pathogenicity and therapeutic perspectives". Nature Reviews Drug Discovery. 9 (3): 237–48. doi:10.1038/nrd3050. PMID 20190788.
- ^ Stefani, M.; Dobson, CM. (November 2003). "Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution". J Mol Med (Berl). 81 (11): 678–99. doi:10.1007/s00109-003-0464-5. PMID 12942175.
- ^ De Felice, FG.; Vieira, MN.; Meirelles, MN.; Morozova-Roche, LA.; Dobson, CM.; Ferreira, ST. (July 2004). "Formation of amyloid aggregates from human lysozyme and its disease-associated variants using hydrostatic pressure". FASEB J. 18 (10): 1099–101. doi:10.1096/fj.03-1072fje. PMID 15155566.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Tanzi, RE.; Bertram, L. (February 2005). "Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective". Cell. 120 (4): 545–55. doi:10.1016/j.cell.2005.02.008. PMID 15734686.
- ^ Brüning, Ansgar; Jückstock, Julia (2015-01-01). "Misfolded proteins: from little villains to little helpers in the fight against cancer". Cancer Molecular Targets and Therapeutics. 5: 47. doi:10.3389/fonc.2015.00047. PMC 4338749. PMID 25759792.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Gething, MJ.; Sambrook, J. (January 1992). "Protein folding in the cell". Nature. 355 (6355): 33–45. doi:10.1038/355033a0. PMID 1731198.
- ^ Roberts, CJ. (December 2007). "Non-native protein aggregation kinetics". Biotechnol Bioeng. 98 (5): 927–38. doi:10.1002/bit.21627. PMID 17705294.
- ^ Cox, David L.; Nelson, Michael M. (2013). Lehninger Principles of Biochemistry. New York: W.H. Freeman. p. 143. ISBN 978-1-4292-3414-6.
- ^ Berke, Sarah J Shoesmith; Paulson, Henry L (2003-06-01). "Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration". Current Opinion in Genetics & Development. 13 (3): 253–261. doi:10.1016/S0959-437X(03)00053-4.
- ^ a b Weaver, Robert F. (2012). Molecular Biology. New York: McGraw-Hill. pp. 122–156, 523–600. ISBN 978-0-07-352532-7.
- ^ a b c d e f Tyedmers, Jens; Mogk, Axel; Bukau, Bernd. "Cellular strategies for controlling protein aggregation". Nature Reviews Molecular Cell Biology. 11 (11): 777–788. doi:10.1038/nrm2993.
- ^ "The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditiselegans". PNAS. 99: 10417–10422. 2002. doi:10.1073/pnas.152161099.
- ^ Zhu, YJ.; Lin, H.; Lal, R. (June 2000). "Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AbetaP-channel-mediated cellular toxicity". FASEB J. 14 (9): 1244–54. PMID 10834946.
- ^ Nilsberth, C.; Westlind-Danielsson, A.; Eckman, CB.; Condron, MM.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, DB.; et al. (September 2001). "The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation". Nat Neurosci. 4 (9): 887–93. doi:10.1038/nn0901-887. PMID 11528419.