- Email: [email protected]
Could it be that neurodegenerative diseases are infectious?
NEUROL-2098; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
International meeting of the French society of neurology & SPILF 2019
Could it be that neurodegenerative diseases are infectious? P. Derkinderen Department of Neurology, CHU de Nantes, boulevard Jacques-Monod, 44093 Nantes, France
info article
abstract
Article history:
The cell-to-cell transmission of the major pathogenic proteins of Parkinson’s disease and
Received 9 May 2019
Alzheimer’s disease is reminiscent of the prion protein, which is defined as a proteinaceous
Received in revised form
infectious particle that causes human and animal transmissible spongiform encephalopa-
10 July 2019
thies. The possibility has raised that the pathogenic proteins of Parkinson’s and Alzheimer’s
Accepted 18 July 2019
disease are infectious, i.e. that they can transmit disease from human to human. In this
Available online xxx
review, we address this question by comparing the similarities and differences between Alzheimer’s disease/Parkinson’s disease pathological proteins and prions and by discussing
Keywords:
the possible consequences for disease transmission risk. # 2019 Elsevier Masson SAS. All rights reserved.
Neurodegenerative disorders Prion Alpha-synuclein Tau Amyloid beta
Current evidence implicates the cell-to-cell transmission of the major pathogenic proteins of neurodegenerative diseases, including Parkinson disease (PD) and Alzheimer disease (AD). This cell-to-cell transmissibility is often called prion-like, because it is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal spongiform encephalopathies. This has raised concerns about the transmission of AD and PD pathological protein aggregates and the possible risk of patient contamination following surgery or transfusion. To address this question, this short article reviews the similarities and differences between AD/PD pathological proteins and prions. After a brief introduction on prions, we provide an overview of the experimental findings and clinical and epidemiological studies that have examined the transmission of protein
aggregation by alpha-synuclein, tau and Ab. Finally, we discuss the possible consequences for disease transmission risk.
1. Back to the basics, infectivity and the prion protein paradigm Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of progressive neurodegenerative disorders that affect both humans and animals. Pathologically, they are characterized by spongiform changes in the brain, neuronal loss, astrocytosis, and the intracerebral buildup of misfolded prion protein [1]. Human prion diseases include Creutzfeldt– Jakob disease, Gerstmann–Stra¨ussler–Scheinker disease,
E-mail addresses: [email protected], [email protected]. https://doi.org/10.1016/j.neurol.2019.07.003 0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
NEUROL-2098; No. of Pages 4
2
revue neurologique xxx (2019) xxx–xxx
Kuru, and fatal insomnias, while in non-human species, they include among others scrapie in sheep, chronic wasting disease of deer and bovine spongiform encephalopathy [2]. In the 70s, Gajdusek showed that human TSEs were transmissible to non-human primates and among humans (reviewed in [3]) and by the 1980s, Prusiner demonstrated that the TSEs infectious agent consists solely of an abnormally folded form of the normal cellular prion protein, and therefore called them ‘‘prions’’ for proteinaceous infectious particle [1]. The prion paradigm posits that, in pathological conditions, misfolded prion proteins aggregate together and induce conformational misfolding in susceptible normal cellular prion protein causing nucleation-dependent and autocatalytic amplification of transmissible prions, a phenomenon referred to as ‘seeding’. Based on their replication mechanism and the observation that prions can be secreted and internalized by cells [4,5], it has been shown prions can transmit misfolding and aggregation (i) at the molecular level; (ii) from one cell to another; (iii) within and between tissues; and (iv) also between individuals. According to the World Health Organization, infectious diseases can be spread, directly or indirectly, from one person to another and are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi (https://www. who.int/topics/infectious_diseases/en/). The infectious nature of prions is well established to transmit disease both within and across species. Early studies showed that brain homogenates from scrapie-infected sheep were capable of transmitting TSEs to mice [6] and that human TSEs were transmissible to non-human primates [7]. In humans, acquired prion disease has been associated with several serious epidemics including Kuru, which affected the native Fore tribes of Papua New Guinea who practiced ritualistic cannibalism and a new form of Creutzfeldt–Jakob disease (variant Creutzfeldt–Jakob disease), which results from the consumption of bovine spongiform encephalopathy-infected beef [8]. In addition, various TSEs cases have been documented following unconventional routes of transmission including among others corneal grafting, the use of inappropriately sterilized surgical equipment, dura mater grafts and use of human cadaveric pituitary derived growth hormone (reviewed in [9]).
2. Do alpha-synuclein, tau and Ab deserve to be called prions? Lewy bodies and neurites, the pathological hallmarks of PD, are primarily composed of alpha-synuclein. The term ‘prionlike’ for alpha-synuclein was first used in 2008, in the discussion of Patrik Brundin’s paper [10], which reported the presence of alpha-synuclein deposits in the transplanted tissue of PD patients who had fetal nigral dopaminergic nerve cells grafted into their striatum: ‘‘On the basis of experimental data, including those showing the acceleration of amyloid deposition after exogenous seeding, the hypothesis of ‘permissive templating’ has been proposed to explain disease propagation along neuronal pathways in neurodegenerative diseases, including Parkinson’s disease. Our observations may provide support for such a hypothesis,
implicating a «prion-like» mechanism’’. These findings are supported by numerous in vitro data, which show that alphasynuclein is capable of traveling from cell to cell. In a seminal paper published in 2005, Lee et al. showed that alphasynuclein, and especially its aggregated forms can be secreted from neurons through unconventional exocytosis [11]. Subsequent work demonstrated that preformed fibrils of extracellular alpha-synuclein are capable of entering neurons thereby promoting recruitment of soluble endogenous alphasynuclein into insoluble deposits (resembling Lewy bodies and neurites) in a mechanism that might be reminiscent of the seeding capacity of prions [12]. In addition to these observations, alpha-synuclein pathology transmission and propagation through neuronal connections have been observed after injection of pathological alpha-synuclein (obtained either from diseased brain homogenates or preformed alphasynuclein fibrils) into the brain or the peripheral autonomic nervous systems of wild-type rodents and non-human primates [13–15]. As a whole, these findings clearly demonstrate that alpha-synuclein has the capacity to transmit misfolding and aggregation at the molecular level, between cells and also within and between tissues, suggesting that it might behave as a prion. The microtubule-associated protein tau is found predominantly in neurons, where it exists as a highly soluble protein that interacts with the cytoskeleton. Under pathological conditions, aberrant assembly of highly phosphorylated tau into insoluble aggregates is observed in a range of neurodegenerative disorders, collectively referred to as tauopathies, including Alzheimer’s disease and progressive supranuclear palsy [16]. One of the first papers suggesting that tau behaves like prions was published in 2009. In this study, Tolnay’s group showed that the intracerebral injection of brain extract from mice with a tau pathology induced the formation and spreading of aggregates made of hyperphosphorylated tau in mice transgenic for human wild-type tau and that the affected brain regions were connected anatomically [17]. These results demonstrated the experimental transmission of tauopathy but it remained to be shown at the molecular and cellular level that tau could be transmitted from cell to cell and promote seeding. This was accomplished subsequently by showing that tau is not only secreted by neurons [18] but also taken up to recruit soluble tau into insoluble aggregates in cultured cells [19]. The assumption that AD might share pathogenic mechanisms with prion diseases has a relatively long history. In 1994, Ridley and Baker were the first to show that the intracerebral injection of AD brain homogenates in marmosets induced senile plaque and amyloid angiopathy in the recipient animals five years after injection [20]. Subsequent experiments showed unequivocally that the active agent is aggregated Ab, and that the ability of Ab to seed as well as the characteristics of the resulting deposits were governed by both the agent and the host [21]. As a whole, these findings clearly demonstrate that the proteins that accumulate in PD and AD have the capacity to alter folding of the corresponding normal protein by corruptive templating (seeding) and to transmit the pathology to experimental animals. These observations support the assumption that these proteins behave like prions, hence
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
NEUROL-2098; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
the name prion-like, prionoids or propagons as proposed by Eisele and Duyckaerts [22]. However, the main question that is still pending is ‘what is the potential infectivity of alphasynuclein, tau and Ab, i.e. what are their abilities to transmit the pathological process between individuals?’
3. Are alpha-synuclein, tau and Ab infectious proteins? Although few studies have addressed this issue, there is currently no evidence of interhuman transmission of pathological alpha-synuclein or tau [23]. Infectivity of Ab through a prion-like mechanism has been postulated at first on the basis of the neuropathological findings in patients with iatrogenic Creutzfeldt–Jakob disease [24] and more recently in young adult individuals with early-onset cerebral amyloid angiopathy who had a history of neurosurgery or other invasive medical procedures [25–28]. In these papers, young adults (aged 30 to 57) developed pathologically-proven cerebral amyloid angiopathy decades after neurosurgery with dura mater grafting or embolization of external carotid artery by dural extracts. The occurrence of cerebral amyloid angiopathy in these young patients strongly suggests iatrogenic interhuman transmission of Ab.
4.
Conclusions
There is now strong evidence that pathological proteins aggregated in PD and AD all behave like prionoids or propagons [22]. Regarding human-to-human transmission, it is likely that Ab can be iatrogenically transmitted from human to human. By contrast, there is no evidence of interhuman transmission of alpha-synuclein or tau lesions but it should be kept in mind that very few studies have addressed this issue and that the long incubation period of PD and AD makes epidemiological and longitudinal studies delicate. As stated in a recent and elegant review on the topic, the precautions taken in neurosurgery to prevent iatrogenic transmission of Creutzfeldt–Jakob disease are likely to prevent the transmission of both AD and PD pathological lesions but it might be also reasonable to exclude AD and PD patients from donor programs [29]. In addition, given the growing experimental research on misfolded proteins in neurodegenerative disorders, it is also important to effectively decontaminate and inactivate the material and surfaces used in research laboratories [30].
Disclosure of interest The author declares that he has no competing interest.
references
[1] Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216:136–44.
[2] Prusiner SB. The prion diseases. Brain Pathol 1998;8:499– 513. [3] Asher DM, Gibbs CJ, Gajdusek DC. Pathogenesis of subacute spongiform encephalopathies. Ann Clin Lab Sci 1976;6:84– 103. [4] Hay B, Prusiner SB, Lingappa VR. Evidence for a secretory form of the cellular prion protein. Biochemistry 1987;26:8110–5. [5] Magalha˜es AC, Baron GS, Lee KS, Steele-Mortimer O, Dorward D, Prado MAM, et al. Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J Neurosci 2005;25:5207–16. http:// dx.doi.org/10.1523/JNEUROSCI.0653-05.2005. [6] Chandler RL. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet 1961;1:1378– 9. [7] Gajdusek DC, Gibbs CJ, Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature 1966;209:794–6. [8] Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921–5. [9] Will RG, Ironside JW. Sporadic and Infectious Human Prion Diseases. Cold Spring Harb Perspect Med 2017;7. http:// dx.doi.org/10.1101/cshperspect.a024364. [10] Li J-Y, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 2008;14:501–3. http://dx.doi.org/ 10.1038/nm1746. [11] Lee H-J, Patel S, Lee S-J. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005;25:6016–24. http://dx.doi.org/10.1523/JNEUROSCI.069205.2005. [12] Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, et al. Exogenous a-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011;72:57–71. http://dx.doi.org/10.1016/ j.neuron.2011.08.033. [13] Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, et al. Pathological a-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012;338:949–53. http://dx.doi.org/10.1126/ science.1227157. [14] Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjo¨rklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 2014;128:805–20. http://dx.doi.org/ 10.1007/s00401-014-1343-6. [15] Recasens A, Dehay B, Bove´ J, Carballo-Carbajal I, Dovero S, Pe´rez-Villalba A, et al. Lewy body extracts from Parkinson disease brains trigger a-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014;75:351–62. http://dx.doi.org/10.1002/ana.24066. [16] Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol 2017;133:665–704. http:// dx.doi.org/10.1007/s00401-017-1707-9. [17] Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009;11:909–13. http://dx.doi.org/10.1038/ncb1901. [18] Pooler AM, Phillips EC, Lau DHW, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep 2013;14:389–94. http:// dx.doi.org/10.1038/embor.2013.15. [19] Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009;284:12845–52. http://dx.doi.org/10.1074/ jbc.M808759200.
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
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[20] Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Induction of beta (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol Neurobiol 1994;8:25–39. http://dx.doi.org/10.1007/ BF02778005. [21] Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 2006;313:1781–4. http://dx.doi.org/10.1126/ science.1131864. [22] Eisele YS, Duyckaerts C. Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 2016;131:5–25. http://dx.doi.org/10.1007/ s00401-015-1516-y. [23] Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM-Y, et al. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 2013;70:462–8. http://dx.doi.org/10.1001/jamaneurol. 2013.1933. [24] Duyckaerts C, Sazdovitch V, Ando K, Seilhean D, Privat N, Yilmaz Z, et al. Neuropathology of iatrogenic CreutzfeldtJakob disease and immunoassay of French cadaversourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology. Acta Neuropathol 2018;135:201–12. http://dx.doi.org/10.1007/s00401-0171791-x.
[25] Banerjee G, Adams ME, Jaunmuktane Z, Alistair Lammie G, Turner B, Wani M, et al. Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura. Ann Neurol 2019;85:284–90. http://dx.doi.org/10.1002/ ana.25407. [26] Hamaguchi T, Komatsu J, Sakai K, Noguchi-Shinohara M, Aoki S, Ikeuchi T, et al. Cerebral hemorrhagic stroke associated with cerebral amyloid angiopathy in young adults about 3 decades after neurosurgeries in their infancy. J Neurol Sci 2019;399:3–5. http://dx.doi.org/10.1016/ j.jns.2019.01.051. [27] Herve´ D, Porche´ M, Cabrejo L, Guidoux C, Tournier-Lasserve E, Nicolas G, et al. Fatal Ab cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years. Acta Neuropathol 2018;135:801–3. http://dx.doi.org/10.1007/ s00401-018-1828-9. [28] Jaunmuktane Z, Quaegebeur A, Taipa R, Viana-Baptista M, Barbosa R, Koriath C, et al. Evidence of amyloid-b cerebral amyloid angiopathy transmission through neurosurgery. Acta Neuropathol 2018;135:671–9. http://dx.doi.org/10.1007/ s00401-018-1822-2. [29] Duyckaerts C, Clavaguera F, Potier M-C. The prion-like propagation hypothesis in Alzheimer’s and Parkinson’s disease. Curr Opin Neurol 2019;32:266–71. http://dx.doi.org/ 10.1097/WCO.0000000000000672. [30] Fenyi A, Coens A, Bellande T, Melki R, Bousset L. Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and A-beta fibrils from laboratory material and surfaces. Sci Rep 2018;8:10788. http://dx.doi.org/10.1038/s41598-018-28856-2.
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
Available online at
ScienceDirect www.sciencedirect.com
International meeting of the French society of neurology & SPILF 2019
Could it be that neurodegenerative diseases are infectious? P. Derkinderen Department of Neurology, CHU de Nantes, boulevard Jacques-Monod, 44093 Nantes, France
info article
abstract
Article history:
The cell-to-cell transmission of the major pathogenic proteins of Parkinson’s disease and
Received 9 May 2019
Alzheimer’s disease is reminiscent of the prion protein, which is defined as a proteinaceous
Received in revised form
infectious particle that causes human and animal transmissible spongiform encephalopa-
10 July 2019
thies. The possibility has raised that the pathogenic proteins of Parkinson’s and Alzheimer’s
Accepted 18 July 2019
disease are infectious, i.e. that they can transmit disease from human to human. In this
Available online xxx
review, we address this question by comparing the similarities and differences between Alzheimer’s disease/Parkinson’s disease pathological proteins and prions and by discussing
Keywords:
the possible consequences for disease transmission risk. # 2019 Elsevier Masson SAS. All rights reserved.
Neurodegenerative disorders Prion Alpha-synuclein Tau Amyloid beta
Current evidence implicates the cell-to-cell transmission of the major pathogenic proteins of neurodegenerative diseases, including Parkinson disease (PD) and Alzheimer disease (AD). This cell-to-cell transmissibility is often called prion-like, because it is reminiscent of the prion protein, which is defined as a proteinaceous infectious particle that causes human and animal spongiform encephalopathies. This has raised concerns about the transmission of AD and PD pathological protein aggregates and the possible risk of patient contamination following surgery or transfusion. To address this question, this short article reviews the similarities and differences between AD/PD pathological proteins and prions. After a brief introduction on prions, we provide an overview of the experimental findings and clinical and epidemiological studies that have examined the transmission of protein
aggregation by alpha-synuclein, tau and Ab. Finally, we discuss the possible consequences for disease transmission risk.
1. Back to the basics, infectivity and the prion protein paradigm Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of progressive neurodegenerative disorders that affect both humans and animals. Pathologically, they are characterized by spongiform changes in the brain, neuronal loss, astrocytosis, and the intracerebral buildup of misfolded prion protein [1]. Human prion diseases include Creutzfeldt– Jakob disease, Gerstmann–Stra¨ussler–Scheinker disease,
E-mail addresses: [email protected], [email protected]. https://doi.org/10.1016/j.neurol.2019.07.003 0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
NEUROL-2098; No. of Pages 4
2
revue neurologique xxx (2019) xxx–xxx
Kuru, and fatal insomnias, while in non-human species, they include among others scrapie in sheep, chronic wasting disease of deer and bovine spongiform encephalopathy [2]. In the 70s, Gajdusek showed that human TSEs were transmissible to non-human primates and among humans (reviewed in [3]) and by the 1980s, Prusiner demonstrated that the TSEs infectious agent consists solely of an abnormally folded form of the normal cellular prion protein, and therefore called them ‘‘prions’’ for proteinaceous infectious particle [1]. The prion paradigm posits that, in pathological conditions, misfolded prion proteins aggregate together and induce conformational misfolding in susceptible normal cellular prion protein causing nucleation-dependent and autocatalytic amplification of transmissible prions, a phenomenon referred to as ‘seeding’. Based on their replication mechanism and the observation that prions can be secreted and internalized by cells [4,5], it has been shown prions can transmit misfolding and aggregation (i) at the molecular level; (ii) from one cell to another; (iii) within and between tissues; and (iv) also between individuals. According to the World Health Organization, infectious diseases can be spread, directly or indirectly, from one person to another and are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi (https://www. who.int/topics/infectious_diseases/en/). The infectious nature of prions is well established to transmit disease both within and across species. Early studies showed that brain homogenates from scrapie-infected sheep were capable of transmitting TSEs to mice [6] and that human TSEs were transmissible to non-human primates [7]. In humans, acquired prion disease has been associated with several serious epidemics including Kuru, which affected the native Fore tribes of Papua New Guinea who practiced ritualistic cannibalism and a new form of Creutzfeldt–Jakob disease (variant Creutzfeldt–Jakob disease), which results from the consumption of bovine spongiform encephalopathy-infected beef [8]. In addition, various TSEs cases have been documented following unconventional routes of transmission including among others corneal grafting, the use of inappropriately sterilized surgical equipment, dura mater grafts and use of human cadaveric pituitary derived growth hormone (reviewed in [9]).
2. Do alpha-synuclein, tau and Ab deserve to be called prions? Lewy bodies and neurites, the pathological hallmarks of PD, are primarily composed of alpha-synuclein. The term ‘prionlike’ for alpha-synuclein was first used in 2008, in the discussion of Patrik Brundin’s paper [10], which reported the presence of alpha-synuclein deposits in the transplanted tissue of PD patients who had fetal nigral dopaminergic nerve cells grafted into their striatum: ‘‘On the basis of experimental data, including those showing the acceleration of amyloid deposition after exogenous seeding, the hypothesis of ‘permissive templating’ has been proposed to explain disease propagation along neuronal pathways in neurodegenerative diseases, including Parkinson’s disease. Our observations may provide support for such a hypothesis,
implicating a «prion-like» mechanism’’. These findings are supported by numerous in vitro data, which show that alphasynuclein is capable of traveling from cell to cell. In a seminal paper published in 2005, Lee et al. showed that alphasynuclein, and especially its aggregated forms can be secreted from neurons through unconventional exocytosis [11]. Subsequent work demonstrated that preformed fibrils of extracellular alpha-synuclein are capable of entering neurons thereby promoting recruitment of soluble endogenous alphasynuclein into insoluble deposits (resembling Lewy bodies and neurites) in a mechanism that might be reminiscent of the seeding capacity of prions [12]. In addition to these observations, alpha-synuclein pathology transmission and propagation through neuronal connections have been observed after injection of pathological alpha-synuclein (obtained either from diseased brain homogenates or preformed alphasynuclein fibrils) into the brain or the peripheral autonomic nervous systems of wild-type rodents and non-human primates [13–15]. As a whole, these findings clearly demonstrate that alpha-synuclein has the capacity to transmit misfolding and aggregation at the molecular level, between cells and also within and between tissues, suggesting that it might behave as a prion. The microtubule-associated protein tau is found predominantly in neurons, where it exists as a highly soluble protein that interacts with the cytoskeleton. Under pathological conditions, aberrant assembly of highly phosphorylated tau into insoluble aggregates is observed in a range of neurodegenerative disorders, collectively referred to as tauopathies, including Alzheimer’s disease and progressive supranuclear palsy [16]. One of the first papers suggesting that tau behaves like prions was published in 2009. In this study, Tolnay’s group showed that the intracerebral injection of brain extract from mice with a tau pathology induced the formation and spreading of aggregates made of hyperphosphorylated tau in mice transgenic for human wild-type tau and that the affected brain regions were connected anatomically [17]. These results demonstrated the experimental transmission of tauopathy but it remained to be shown at the molecular and cellular level that tau could be transmitted from cell to cell and promote seeding. This was accomplished subsequently by showing that tau is not only secreted by neurons [18] but also taken up to recruit soluble tau into insoluble aggregates in cultured cells [19]. The assumption that AD might share pathogenic mechanisms with prion diseases has a relatively long history. In 1994, Ridley and Baker were the first to show that the intracerebral injection of AD brain homogenates in marmosets induced senile plaque and amyloid angiopathy in the recipient animals five years after injection [20]. Subsequent experiments showed unequivocally that the active agent is aggregated Ab, and that the ability of Ab to seed as well as the characteristics of the resulting deposits were governed by both the agent and the host [21]. As a whole, these findings clearly demonstrate that the proteins that accumulate in PD and AD have the capacity to alter folding of the corresponding normal protein by corruptive templating (seeding) and to transmit the pathology to experimental animals. These observations support the assumption that these proteins behave like prions, hence
Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003
NEUROL-2098; No. of Pages 4 revue neurologique xxx (2019) xxx–xxx
the name prion-like, prionoids or propagons as proposed by Eisele and Duyckaerts [22]. However, the main question that is still pending is ‘what is the potential infectivity of alphasynuclein, tau and Ab, i.e. what are their abilities to transmit the pathological process between individuals?’
3. Are alpha-synuclein, tau and Ab infectious proteins? Although few studies have addressed this issue, there is currently no evidence of interhuman transmission of pathological alpha-synuclein or tau [23]. Infectivity of Ab through a prion-like mechanism has been postulated at first on the basis of the neuropathological findings in patients with iatrogenic Creutzfeldt–Jakob disease [24] and more recently in young adult individuals with early-onset cerebral amyloid angiopathy who had a history of neurosurgery or other invasive medical procedures [25–28]. In these papers, young adults (aged 30 to 57) developed pathologically-proven cerebral amyloid angiopathy decades after neurosurgery with dura mater grafting or embolization of external carotid artery by dural extracts. The occurrence of cerebral amyloid angiopathy in these young patients strongly suggests iatrogenic interhuman transmission of Ab.
4.
Conclusions
There is now strong evidence that pathological proteins aggregated in PD and AD all behave like prionoids or propagons [22]. Regarding human-to-human transmission, it is likely that Ab can be iatrogenically transmitted from human to human. By contrast, there is no evidence of interhuman transmission of alpha-synuclein or tau lesions but it should be kept in mind that very few studies have addressed this issue and that the long incubation period of PD and AD makes epidemiological and longitudinal studies delicate. As stated in a recent and elegant review on the topic, the precautions taken in neurosurgery to prevent iatrogenic transmission of Creutzfeldt–Jakob disease are likely to prevent the transmission of both AD and PD pathological lesions but it might be also reasonable to exclude AD and PD patients from donor programs [29]. In addition, given the growing experimental research on misfolded proteins in neurodegenerative disorders, it is also important to effectively decontaminate and inactivate the material and surfaces used in research laboratories [30].
Disclosure of interest The author declares that he has no competing interest.
references
[1] Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216:136–44.
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Please cite this article in press as: Derkinderen P. Could it be that neurodegenerative diseases are infectious?. Revue neurologique (2019), https:// doi.org/10.1016/j.neurol.2019.07.003