Transmissible Proteins: Expanding the Prion Heresy
2012; Cell Press; Volume: 149; Issue: 5 Linguagem: Inglês
10.1016/j.cell.2012.05.007
ISSN1097-4172
Autores Tópico(s)RNA regulation and disease
ResumoThe once heretical concept that a misfolded protein is the infectious agent responsible for prion diseases is now widely accepted. Recent exciting research has led not only to the end of the skepticism that proteins can transmit disease, but also to expanding the concept that transmissible proteins might be at the root of some of the most prevalent human illnesses. At the same time, the idea that biological information can be transmitted by propagation of protein (mis)folding raises the possibility that heritable protein agents may be operating as epigenetic factors in normal biological functions and participating in evolutionary adaptation. The once heretical concept that a misfolded protein is the infectious agent responsible for prion diseases is now widely accepted. Recent exciting research has led not only to the end of the skepticism that proteins can transmit disease, but also to expanding the concept that transmissible proteins might be at the root of some of the most prevalent human illnesses. At the same time, the idea that biological information can be transmitted by propagation of protein (mis)folding raises the possibility that heritable protein agents may be operating as epigenetic factors in normal biological functions and participating in evolutionary adaptation. The discovery that proteins can behave like infectious agents to transmit disease is a significant milestone in biology. The unorthodox prion hypothesis was proposed decades ago to explain the surprising transmission mechanisms of a group of rare diseases known as transmissible spongiform encephalopathies (TSEs), or prion diseases (Griffith, 1967Griffith J.S. Self-replication and scrapie.Nature. 1967; 215: 1043-1044Crossref PubMed Scopus (898) Google Scholar, Prusiner, 1982Prusiner S.B. Novel proteinaceous infectious particles cause scrapie.Science. 1982; 216: 136-144Crossref PubMed Scopus (4097) Google Scholar). The prion hypothesis states that the infectious agent in TSEs is composed exclusively of a misfolded form of the prion protein (PrPSc), which replicates in infected individuals by transforming the normal version of the prion protein (PrPC) into more of the misfolded isoform (Prusiner, 1998Prusiner S.B. Prions.Proc. Natl. Acad. Sci. USA. 1998; 95: 13363-13383Crossref PubMed Scopus (5131) Google Scholar). This hypothesis remained controversial for decades, but recent studies have settled all doubts by demonstrating that infectious material can be generated in vitro, in the absence of genetic material, by replication of the protein misfolding process (Legname et al., 2004Legname G. Baskakov I.V. Nguyen H.O. Riesner D. Cohen F.E. DeArmond S.J. Prusiner S.B. Synthetic mammalian prions.Science. 2004; 305: 673-676Crossref PubMed Scopus (907) Google Scholar, Castilla et al., 2005Castilla J. Saá P. Hetz C. Soto C. In vitro generation of infectious scrapie prions.Cell. 2005; 121: 195-206Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar, Deleault et al., 2007Deleault N.R. Harris B.T. Rees J.R. Supattapone S. Formation of native prions from minimal components in vitro.Proc. Natl. Acad. Sci. USA. 2007; 104: 9741-9746Crossref PubMed Scopus (518) Google Scholar, Wang et al., 2010Wang F. Wang X. Yuan C.-G. Ma J. Generating a prion with bacterially expressed recombinant prion protein.Science. 2010; 327: 1132-1135Crossref PubMed Scopus (562) Google Scholar). Despite the obvious differences between prions and conventional infectious micro-organisms (such as bacteria or viruses), prions exhibit the typical characteristics of bona fide infectious agents, namely, exponential multiplication in an appropriate host; transmission between individuals by various routes, including food borne and blood borne; titration by infectivity bioassays; resistance to biological clearance mechanisms; penetration of biological membrane barriers; “mutation” by structural changes forming diverse strains; and transmission controlled by species barriers. Although prions fulfill the Koch's postulates for infectious agents, it remains surprising that a single protein possesses the complexity and flexibility required to act like living micro-organisms that transmit disease. Prion replication requires exposure to tiny quantities of PrPSc, present in the infectious material, to trigger the autocatalytic conversion of host PrPC to PrPSc. This process follows a crystallization-like model in which the infectious particle (a small PrPSc aggregate) acts as a nucleus to recruit monomeric PrPC into the growing PrPSc polymer (Lansbury and Caughey, 1995Lansbury Jr., P.T. Caughey B. The chemistry of scrapie infection: implications of the ‘ice 9’ metaphor.Chem. Biol. 1995; 2: 1-5Abstract Full Text PDF PubMed Scopus (142) Google Scholar). A key step in prion replication is the breakage of large PrPSc aggregates into many smaller seeding-competent polymers that amplify the prion replication process, resulting in the exponential accumulation of PrPSc (Saborio et al., 2001Saborio G.P. Permanne B. Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding.Nature. 2001; 411: 810-813Crossref PubMed Scopus (1011) Google Scholar). This seeding-nucleation mechanism of prion propagation has been reproduced in vitro to “cultivate” prions with infectious properties when inoculated into animals (Castilla et al., 2005Castilla J. Saá P. Hetz C. Soto C. In vitro generation of infectious scrapie prions.Cell. 2005; 121: 195-206Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar, Deleault et al., 2007Deleault N.R. Harris B.T. Rees J.R. Supattapone S. Formation of native prions from minimal components in vitro.Proc. Natl. Acad. Sci. USA. 2007; 104: 9741-9746Crossref PubMed Scopus (518) Google Scholar, Wang et al., 2010Wang F. Wang X. Yuan C.-G. Ma J. Generating a prion with bacterially expressed recombinant prion protein.Science. 2010; 327: 1132-1135Crossref PubMed Scopus (562) Google Scholar). Additional research is needed to elucidate the precise mechanisms and cellular factors required for prion replication in vivo as well as the detailed structure of the infectious folding of the prion protein (Soto, 2011Soto C. Prion hypothesis: the end of the controversy?.Trends Biochem. Sci. 2011; 36: 151-158Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). The transformation of a natively folded protein into a misfolded, toxic form that causes tissue damage and disease is not a mechanism that is exclusive to prion diseases. Misfolded protein aggregates are implicated in more than 20 human diseases, collectively called protein misfolding disorders (PMDs), including highly prevalent and insidious illnesses such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes (Soto, 2003Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases.Nat. Rev. Neurosci. 2003; 4: 49-60Crossref PubMed Scopus (1101) Google Scholar, Chiti and Dobson, 2006Chiti F. Dobson C.M. Protein misfolding, functional amyloid, and human disease.Annu. Rev. Biochem. 2006; 75: 333-366Crossref PubMed Scopus (5112) Google Scholar). Although the proteins implicated in each of these pathologies and the clinical manifestations of the diseases differ, the molecular mechanism of protein misfolding is strikingly similar. Unfortunately, despite the extensive knowledge about the molecular basis of these disorders, the factors that trigger protein misfolding and initiate the pathology remain unknown. The protein misfolding processes in other PMDs share the same replication mechanism and result in the formation of similar intermediates and end products as the PrPC-to-PrPSc conversion in prion diseases. The protein conformational changes associated with the pathogenesis of PMDs produce β sheet-rich oligomers that are partially resistant to proteolysis and have a high tendency to form amyloid-like aggregates (Soto, 2003Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases.Nat. Rev. Neurosci. 2003; 4: 49-60Crossref PubMed Scopus (1101) Google Scholar, Chiti and Dobson, 2006Chiti F. Dobson C.M. Protein misfolding, functional amyloid, and human disease.Annu. Rev. Biochem. 2006; 75: 333-366Crossref PubMed Scopus (5112) Google Scholar). Interestingly, the available data indicate that misfolding and aggregation processes in PMDs follow a seeding-nucleation mechanism (Harper and Lansbury, 1997Harper J.D. Lansbury Jr., P.T. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins.Annu. Rev. Biochem. 1997; 66: 385-407Crossref PubMed Scopus (1412) Google Scholar, O'Nuallain et al., 2004O'Nuallain B. Williams A.D. Westermark P. Wetzel R. Seeding specificity in amyloid growth induced by heterologous fibrils.J. Biol. Chem. 2004; 279: 17490-17499Crossref PubMed Scopus (338) Google Scholar, Soto et al., 2006Soto C. Estrada L. Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates.Trends Biochem. Sci. 2006; 31: 150-155Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). The process is initiated by the slow interaction between protein monomers to form a stable oligomeric nucleus (or seed) around which a faster phase of polymeric elongation occurs. The limiting step in this process is nuclei formation, and the rate of misfolding and aggregation depends upon the number of seeds produced (Harper and Lansbury, 1997Harper J.D. Lansbury Jr., P.T. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins.Annu. Rev. Biochem. 1997; 66: 385-407Crossref PubMed Scopus (1412) Google Scholar). As described above, the key element that makes PrPSc infectious is its ability to act as a seed to induce the conversion of PrPC to PrPSc (Lansbury and Caughey, 1995Lansbury Jr., P.T. Caughey B. The chemistry of scrapie infection: implications of the ‘ice 9’ metaphor.Chem. Biol. 1995; 2: 1-5Abstract Full Text PDF PubMed Scopus (142) Google Scholar, Soto et al., 2006Soto C. Estrada L. Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates.Trends Biochem. Sci. 2006; 31: 150-155Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). In the same way as PrPSc, extensive evidence indicates that oligomeric structures of the proteins implicated in PMDs are able to seed accelerated misfolding and aggregation of the natively folded monomeric protein (O'Nuallain et al., 2004O'Nuallain B. Williams A.D. Westermark P. Wetzel R. Seeding specificity in amyloid growth induced by heterologous fibrils.J. Biol. Chem. 2004; 279: 17490-17499Crossref PubMed Scopus (338) Google Scholar). Given the striking similarities between the pathological mechanisms of TSEs and other PMDs, a critical question is whether other PMDs are transmissible and whether the proteins implicated may also behave as infectious agents. In this Perspective, we refer to the proteins able to propagate biological information by the prion principle as “transmissible proteins” to avoid the misunderstanding produced by calling them prions. It is important to emphasize that the concept of transmissible proteins does not necessarily imply that the outcome of the transmission of protein misfolding should be a disease, but as described in the sections below, transmissible proteins could also be implicated in normal biological processes or could even provide an evolutionary tool for environmental adaptation. The putative transmissibility of PMDs has not been analyzed in detail, but the lack of epidemiological data supporting disease transmission is often used to rule out an infectious origin for these diseases. However, it is likely that, without the fortuitous transmission of sheep scrapie in 1937 (Cullie and Chelle, 1939Cullie J. Chelle P.L. Experimental transmission of trembling to the goat.Comptes Rendus des Seances de l'Academie des Sciences. 1939; 208: 1058-1160Google Scholar) or Gadjusek's milestone discovery of kuru transmission by cannibalism (Gajdusek et al., 1966Gajdusek D.C. Gibbs C.J. Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees.Nature. 1966; 209: 794-796Crossref PubMed Scopus (621) Google Scholar), an infectious origin for TSEs might have never been suspected. Indeed, epidemiological studies of relatives and people in contact with Creutzfeldt-Jakob disease (CJD) patients consistently produce negative results. Epidemiological tracking of an infectious origin for these diseases can be complicated by variable and extended time between exposure to the infectious agent and the onset of clinical symptoms, especially when this interval can be decades, as is typical for human TSEs. A series of recent studies has provided experimental evidence for prion-like mechanisms of pathological transmission in various common neurodegenerative diseases (Table 1). Alzheimer's disease (AD) is associated with the misfolding and aggregation of two proteins: amyloid-β (Aβ) accumulation in extracellular amyloid plaques and hyperphosphorylated tau, which forms neurofibrillary tangles inside of neurons. To assess the possibility that AD pathology might be transmissible by a prion-like mechanism, transgenic mice expressing the human amyloid protein were injected intracerebrally with diluted brain homogenates derived from AD patients (Kane et al., 2000Kane M.D. Lipinski W.J. Callahan M.J. Bian F. Durham R.A. Schwarz R.D. Roher A.E. Walker L.C. Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.J. Neurosci. 2000; 20: 3606-3611Crossref PubMed Google Scholar, Meyer-Luehmann et al., 2006Meyer-Luehmann M. Coomaraswamy J. Bolmont T. Kaeser S. Schaefer C. Kilger E. Neuenschwander A. Abramowski D. Frey P. Jaton A.L. et al.Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (781) Google Scholar). The results clearly showed accelerated Aβ-deposition in the brain of inoculated animals. Control experiments depleting the material from Aβ aggregates or inactivating their conformation did not produce acceleration of the pathology, indicating that preformed Aβ aggregates are required to seed amyloid plaque deposition in vivo (Meyer-Luehmann et al., 2006Meyer-Luehmann M. Coomaraswamy J. Bolmont T. Kaeser S. Schaefer C. Kilger E. Neuenschwander A. Abramowski D. Frey P. Jaton A.L. et al.Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (781) Google Scholar). Reminiscent to prions, seeding-competent Aβ aggregates are partially resistant to proteolysis and consist of a continuum of various sizes, with the most efficient seeds being smaller Aβ oligomers (Langer et al., 2011Langer F. Eisele Y.S. Fritschi S.K. Staufenbiel M. Walker L.C. Jucker M. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition.J. Neurosci. 2011; 31: 14488-14495Crossref PubMed Scopus (189) Google Scholar). Oligomerization may be enhanced by posttranslational modifications, such as pyroglutamylation, promoting the formation of the first seeds that then propagate in a prion-like manner (Nussbaum et al., 2012Nussbaum J.M. Schilling S. Cynis H. Silva A. Swanson E. Wangsanut T. Tayler K. Wiltgen B. Hatami A. Ronicke R. et al.Prion-like behavior and tau-dependent cytotoxicity of pyroglutamylated amyloid-β.Nature. 2012; (Published online May 2, 2012)https://doi.org/10.1038/nature11060Crossref PubMed Scopus (323) Google Scholar). However, unlike prion disease, which can be induced de novo in animals that do not spontaneously develop the pathology, the induction of Aβ deposition observed in these studies only represents an acceleration by a few months of the spontaneous process that is set to occur by introduction of the mutant gene. Recent experiments performed in transgenic animals expressing low levels of wild-type human amyloid precursor protein find that disease alterations can be induced in animals that, without exposure to this material, will never develop the pathology during their entire life span (Morales et al., 2011Morales R. Duran-Aniotz C. Castilla J. Estrada L.D. Soto C. De novo induction of amyloid-β deposition in vivo.Mol. Psychiatry. 2011; (Published online October 4, 2011)https://doi.org/10.1038/mp.2011.120Crossref PubMed Scopus (146) Google Scholar, Rosen et al., 2012Rosen R.F. Fritz J.J. Dooyema J. Cintron A.F. Hamaguchi T. Lah J.J. LeVine 3rd, H. Jucker M. Walker L.C. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats.J. Neurochem. 2012; 120: 660-666Crossref PubMed Scopus (104) Google Scholar), getting much closer to the bona fide prion transmission observed in TSEs. Another important step forward in the similarities between Aβ and prion transmission has been the demonstration that AD brain abnormalities can be induced by intraperitoneal inoculation of transgenic mice with Alzheimer's brain extracts (Eisele et al., 2010Eisele Y.S. Obermüller U. Heilbronner G. Baumann F. Kaeser S.A. Wolburg H. Walker L.C. Staufenbiel M. Heikenwalder M. Jucker M. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.Science. 2010; 330: 980-982Crossref PubMed Scopus (457) Google Scholar). This finding suggests that seeds acquired by peripheral route of exposure may induce disease in the brain. However, because the source of misfolded Aβ used in these experiments is sick brain homogenates, the relevance of these findings for AD transmissibility is uncertain.Table 1Potential Candidate Disease-Associated Transmissible ProteinsDiseaseProtein (Location)Experimental TransmissionNatural TransmissionReferencesaThere are several more references that could have been cited, but due to space constraints, only the most relevant articles are listed.Prion diseasesPrPSc (extracellular)infectious in diverse animal species by various routesinfectious in diverse species by various routes(Prusiner, 1998Prusiner S.B. Prions.Proc. Natl. Acad. Sci. USA. 1998; 95: 13363-13383Crossref PubMed Scopus (5131) Google Scholar, Aguzzi and Calella, 2009Aguzzi A. Calella A.M. Prions: protein aggregation and infectious diseases.Physiol. Rev. 2009; 89: 1105-1152Crossref PubMed Scopus (384) Google Scholar)Alzheimer's diseaseAβ (extracellular)induction of pathology in transgenic mice by intracerebral and intraperitoneal inoculationnot shown(Kane et al., 2000Kane M.D. Lipinski W.J. Callahan M.J. Bian F. Durham R.A. Schwarz R.D. Roher A.E. Walker L.C. Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.J. Neurosci. 2000; 20: 3606-3611Crossref PubMed Google Scholar, Meyer-Luehmann et al., 2006Meyer-Luehmann M. Coomaraswamy J. Bolmont T. Kaeser S. Schaefer C. Kilger E. Neuenschwander A. Abramowski D. Frey P. Jaton A.L. et al.Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (781) Google Scholar, Eisele et al., 2010Eisele Y.S. Obermüller U. Heilbronner G. Baumann F. Kaeser S.A. Wolburg H. Walker L.C. Staufenbiel M. Heikenwalder M. Jucker M. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.Science. 2010; 330: 980-982Crossref PubMed Scopus (457) Google Scholar, Morales et al., 2011Morales R. Duran-Aniotz C. Castilla J. Estrada L.D. Soto C. De novo induction of amyloid-β deposition in vivo.Mol. Psychiatry. 2011; (Published online October 4, 2011)https://doi.org/10.1038/mp.2011.120Crossref PubMed Scopus (146) Google Scholar)Parkinson's diseaseα-synuclein (cytoplasmatic)cell-to-cell and host-to-graft spreading in animal models and transmission by intracerebral inoculationhost-to-graft spreading in humans(Desplats et al., 2009Desplats P. Lee H.J. Bae E.J. Patrick C. Rockenstein E. Crews L. Spencer B. Masliah E. Lee S.J. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein.Proc. Natl. Acad. Sci. USA. 2009; 106: 13010-13015Crossref PubMed Scopus (1122) Google Scholar, Luk et al., 2009Luk K.C. Song C. O'Brien P. Stieber A. Branch J.R. Brunden K.R. 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Steiner J.A. Pieri L. Paul G. Outeiro T.F. Melki R. Kallunki P. Fog K. et al.α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells.J. Clin. Invest. 2011; 121: 715-725Crossref PubMed Scopus (631) Google Scholar, Luk et al., 2012Luk K.C. Kehm V.M. Zhang B. O'Brien P. Trojanowski J.Q. Lee V.M. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice.J. Exp. Med. 2012; (Published online April 16, 2012)https://doi.org/10.1084/jem.20112457Crossref PubMed Scopus (746) Google Scholar)Huntington's diseaseHuntingtin (nuclear)cell-to-cell spreading in culturenot shown(Ren et al., 2009Ren P.H. Lauckner J.E. Kachirskaia I. Heuser J.E. Melki R. Kopito R.R. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates.Nat. Cell Biol. 2009; 11: 219-225Crossref PubMed Scopus (346) Google Scholar)TauopathiesTau (cytoplasmatic)cell-to-cell spreading in culture and transmission in transgenic mice by intracerebral inoculationnot shown(Clavaguera et al., 2009Clavaguera F. Bolmont T. Crowther R.A. Abramowski D. Frank S. Probst A. Fraser G. Stalder A.K. Beibel M. Staufenbiel M. et al.Transmission and spreading of tauopathy in transgenic mouse brain.Nat. Cell Biol. 2009; 11: 909-913Crossref PubMed Scopus (1264) Google Scholar, Frost et al., 2009Frost B. Jacks R.L. Diamond M.I. Propagation of tau misfolding from the outside to the inside of a cell.J. Biol. Chem. 2009; 284: 12845-12852Crossref PubMed Scopus (857) Google Scholar, Nonaka et al., 2010Nonaka T. Watanabe S.T. Iwatsubo T. Hasegawa M. Seeded aggregation and toxicity of alpha-synuclein and tau: cellular models of neurodegenerative diseases.J. Biol. Chem. 2010; 285: 34885-34898Crossref PubMed Scopus (246) Google Scholar, Guo and Lee, 2011Guo J.L. Lee V.M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles.J. Biol. Chem. 2011; 286: 15317-15331Crossref PubMed Scopus (434) Google Scholar, de Calignon et al., 2012de Calignon A. Polydoro M. Suárez-Calvet M. William C. Adamowicz D.H. Kopeikina K.J. Pitstick R. Sahara N. Ashe K.H. Carlson G.A. et al.Propagation of tau pathology in a model of early Alzheimer's disease.Neuron. 2012; 73: 685-697Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, Liu et al., 2012Liu L. Drouet V. Wu J.W. Witter M.P. Small S.A. Clelland C. Duff K. Trans-synaptic spread of tau pathology in vivo.PLoS ONE. 2012; 7: e31302Crossref PubMed Scopus (737) Google Scholar)Secondary amyloidosisAmyloid-A (extracellular)acceleration of pathology in mice by various routes of administrationpossible transmission to captive cheetah(Lundmark et al., 2002Lundmark K. Westermark G.T. Nyström S. Murphy C.L. Solomon A. Westermark P. Transmissibility of systemic amyloidosis by a prion-like mechanism.Proc. Natl. Acad. Sci. USA. 2002; 99: 6979-6984Crossref PubMed Scopus (234) Google Scholar, Zhang et al., 2008Zhang B. Une Y. Fu X. Yan J. Ge F. Yao J. Sawashita J. Mori M. Tomozawa H. Kametani F. Higuchi K. Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease.Proc. Natl. Acad. Sci. USA. 2008; 105: 7263-7268Crossref PubMed Scopus (93) Google Scholar)Mouse senile amyloidosisApolipoprotein A (extracellular)acceleration of pathology in mice by various routes of administrationtransmission to mice in the same cage by feces consumption(Xing et al., 2001Xing Y. Nakamura A. Chiba T. Kogishi K. Matsushita T. Li F. Guo Z. Hosokawa M. Mori M. Higuchi K. Transmission of mouse senile amyloidosis.Lab. Invest. 2001; 81: 493-499Crossref PubMed Scopus (92) Google Scholar, Korenaga et al., 2006Korenaga T. Yan J. Sawashita J. Matsushita T. Naiki H. Hosokawa M. Mori M. Higuchi K. Fu X. Transmission of amyloidosis in offspring of mice with AApoAII amyloidosis.Am. J. Pathol. 2006; 168: 898-906Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar)a There are several more references that could have been cited, but due to space constraints, only the most relevant articles are listed. Open table in a new tab Various studies have been also performed to analyze the transmission by seeding of tau aggregates, the other typical feature of AD, which is also found in other neurodegenerative diseases, collectively called tauopathies (e.g., fronto-temporal dementia, chronic traumatic encephalopathy, etc). Intracerebral injection of brain extract containing tau aggregates into transgenic mice expressing human wild-type tau that do not form aggregates spontaneously induced the assembly of native tau into misfolded aggregates in recipient mice (Clavaguera et al., 2009Clavaguera F. Bolmont T. Crowther R.A. Abramowski D. Frank S. Probst A. Fraser G. Stalder A.K. Beibel M. Staufenbiel M. et al.Transmission and spreading of tauopathy in transgenic mouse brain.Nat. Cell Biol. 2009; 11: 909-913Crossref PubMed Scopus (1264) Google Scholar). Interestingly, the pathology spreads over time beyond the site of injection to anatomically connected neighboring brain regions (Clavaguera et al., 2009Clavaguera F. Bolmont T. Crowther R.A. Abramowski D. Frank S. Probst A. Fraser G. Stalder A.K. Beibel M. Staufenbiel M. et al.Transmission and spreading of tauopathy in transgenic mouse brain.Nat. Cell Biol. 2009; 11: 909-913Crossref PubMed Scopus (1264) Google Scholar). Unlike Aβ and PrPSc, tau aggregates are located in the cytoplasm, suggesting that, in this case, protein misfolding is transmitted between cells. This hypothesis is further supported by in vitro studies of cultured cells in which extracellular tau aggregates were taken up and induced the misfolding and aggregation of intracellular tau (Frost et al., 2009Frost B. Jacks R.L. Diamond M.I. Propagation of tau misfolding from the outside to the inside of a cell.J. Biol. Chem. 2009; 284: 12845-12852Crossref PubMed Scopus (857) Google Scholar, Nonaka et al., 2010Nonaka T. Watanabe S.T. Iwatsubo T. Hasegawa M. Seeded aggregation and toxicity of alpha-synuclein and tau: cellular models of neurodegenerative diseases.J. Biol. Chem. 2010; 285: 34885-34898Crossref PubMed Scopus (246) Google Scholar, Guo and Lee, 2011Guo J.L. Lee V.M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles.J. Biol. Chem. 2011; 286: 15317-15331Crossref PubMed Scopus (434) Google Scholar). These intracellular tau aggregates also spread among cells to extend the pathology to the entire culture. Moreover, recent studies using a transgenic mice overexpressing human mutant tau only in a restricted area of the entorhinal cortex showed that the pathology initiated in this region spread throughout the brain even to areas without detectable human tau expression (de Calignon et al., 2012de Calignon A. Polydoro M. Suárez-Calvet M. William C. Adamowicz D.H. Kopeikina K.J. Pitstick R. Sahara N. Ashe K.H. Carlson G.A. et al.Propagation of tau pathology in a model of early Alzheimer's disease.Neuron. 2012; 73: 685-697Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, Liu et al., 2012Liu L. Drouet V. Wu J.W. Witter M.P. Small S.A. Clelland C. Duff K. Trans-synaptic spread of tau pathology in vivo.PLoS ONE. 2012; 7: e31302Crossref PubMed Scopus (737) Google Scholar). The progressive accumulation of tau aggregates in these animals leads to synaptic degeneration and later to axonal damage and neuronal death. Several exciting neuropathological studies in Parkinson's disease (PD) patients additionally support the hypothesis that prion-like spreading of the pathology is a common mechanism in PMDs. PD is characterized by the accumulation of intracytoplasmic aggregates (termed Lewy bodies) made of α-synuclein and primarily located in the substantia nigra. Autopsies of PD patients who received grafts from healthy embryonic neurons many years before showed that some transplanted neurons contained α-synuclein aggregates (Li et al., 2008Li J.Y. Englund E. Holton J.L. Soulet D. Hagell P. Lees A.J. Lashley T. Quinn N.P. Rehncrona S. Björklund A. et al.Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.Nat. Med. 2008; 14: 501-503Crossref PubMed Scopus (1342) Google Scholar, Kordower et al., 2008Kordower J.H. Chu Y. Hauser R.A. Freeman T.B. Olanow C.W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.Nat. Med. 2008; 14: 504-506Crossref PubMed Sc
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