Skip to main content

Does a prion-like mechanism play a major role in the apparent spread of α-synuclein pathology?


Parkinson's disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function. A hallmark of Parkinson's disease is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein α-synuclein. The presence of α-synuclein brain aggregates is observed in several neurodegenerative diseases, including dementia with Lewy bodies and Lewy body variant of Alzheimer's disease. These disorders, as a group, are termed synucleinopathies. Mounting evidence indicates that α-synuclein amyloid pathology may spread during disease progression by a prion-like (self-templating alteration in protein conformation) mechanism. Clear in vitro and cell culture data demonstrate that amyloidogenic α-synuclein can readily induce the conversion of other α-synuclein molecules into this conformation. Some data from experimental mouse studies and autopsied brain analyses also are consistent with the notion that a self-promoting process of α-synuclein amyloid inclusion formation may lead to a progressive spread of disease in vivo. However, as pointed out in this review, there are alternative explanations and interpretations for these findings. Therefore, from a therapeutic perspective, it is critical to determine the relative importance and contribution of α-synuclein prionlike spread in disease before embarking on elaborate efforts to target this putative pathogenic mechanism.

Parkinson's disease and related disorders

Parkinson's disease (PD) is the second most common neurodegenerative disease in the developing world, affecting 1% of the population over 65 years of age and 4% to 5% over 85 years of age. It is characterized clinically by resting tremor, bradykinesia, postural instability, and muscle rigidity [1, 2]. These motor impairments have been attributed largely to a progressive and extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) [35]. PD is associated with a range of other progressive clinical manifestations such as dementia, autonomic dysfunction, depression, seborrhea, sleep disturbance, and sensory symptoms, which most likely are associated with the demise of additional specific neuronal populations [2, 69]. Although some therapeutic (for example, Levodopa) and surgical (for example, deep brain stimulation) interventions can alleviate some of the motor symptoms of PD, there is still no treatment to prevent disease progression. In addition to displaying neuronal loss and neuro-inflammation, most PD brains display the presence of intracytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs) in some of the remaining dopaminergic neurons of the SNpc, but many other neuronal populations are also affected [912]. LBs and LNs are formed as a result of the aberrant amyloid-type aggregation of the neuronal presynaptic protein α-synuclein [1214]. α-Synuclein neuronal inclusions can present in a spectrum of neurodegenerative disorders, termed synucleinopathies, as exemplified by the more widespread presentation of LBs and LNs in the brains of patients with the disorder dementia with LBs (DLB) [12, 13]. DLB often presentscon currently with Alzheimer's disease pathological markers (that is, neurofibrillary tangles and Aβ amyloid plaques), a disease entity sometimes referred to as the LB variant of Alzheimer's disease. There is also evidence that Aβ and neurofibrillary tangle pathologies can spread in a similar prion-type mechanism as α-synuclein and that α-synuclein may cross-seed both of these pathologies [15], but in this review we will focus only on the findings directly involving α-synuclein.

Etiology of Parkinson's disease

Although PD used to be viewed predominantly as an idiopathic disease and most cases are still sporadic, many gene defects that can cause PD have been identified (reviewed in [1618]). Indeed, missense mutations in the α-synuclein (SNCA) gene were the first genetic causes of PD identified and this finding led to a disease paradigm shift toward the importance of the aberrant aggregation of this protein in the etiology of PD. To date, three missense mutations (A53T, A30P, and E46K) have been identified and linked to PD or DLB [1921]. In addition, short chromosomal duplications or trisomies containing the SCNA gene, plus relatively short flanking regions on chromosome 4, were discovered in patients with PD or DLB [22, 23], indicating that a 50% increase in the expression of α-synuclein is sufficient to cause disease. Although the precise mechanism of toxicity of α-synuclein is still debated, most evidence indicates that some form of protein aggregation is involved [13, 24].

Evidence for a prion/spreading mechanism of α-synuclein pathology

The cause of disease progression in PD and DLB has long been elusive, but recent findings suggest that α-synuclein aggregation may proceed via a 'prion-like' mechanism that leads to a spreading of α-synuclein pathology. The term 'prion-like' is used because there is no evidence that α-synuclein aggregates are transmitted between individuals (that is, there is no evidence for infectability), but as reviewed below, α-synuclein aggregation can clearly seed and self-template in vitro and in cultured cells under conditions that favor the entry of preformed amyloid intocells. Furthermore, it may be able to propagate between cells.

Although α-synuclein was viewed typically as a cytoplasmic protein, investigators have shown that both soluble and aggregated α-synuclein can be released from cells [25, 26] and that α-synuclein is present in brain interstitial fluid, cerebrospinal fluid, and blood plasma [2630]. Furthermore, recent studies have demonstrated the ability of α-synuclein to be imported or exported across cell membranes [3134] and to be transferred between host and grafted neurons in mouse brains [33, 35, 36].

It is well established that in vitro α-synuclein aggregation into amyloid is a nucleation-dependent process and can be greatly induced by the addition of a 'seed' or 'nucleus' of pre-aggregated α-synuclein [37, 38]. Cellular studies have shown that the entry of a small amount of preformed α-synuclein fibrils using reagents that promote the entry of these seeds across the plasma membrane can very efficiently induce the formation of large intracellular amyloid inclusions [3941]. More recently, it was shown that the simple addition of extra-cellular α-synuclein fibrils to primary neurons can also induce the formation of intracellular α-synuclein inclusions [42]. Collectively, these studies suggest that α-synuclein amyloid formation may have the ability to spread between cells, although in a robust cellular model of seeded intracellular α-synuclein inclusion formation, it was not possible to observe transmission or propagation of α-synuclein amyloid between cells [40].

A prion-like spreading of α-synuclein pathology is consistent with the Braak staging of disease that appears to follow neuroanatomical pathways [43]. This staging is based on the semi-quantitative immunocytochemical analysis of brain α-synuclein pathology distribution in patients with PD and age-matched controls and indicates a temporal sequence or stages of ascending severity. Other studies also suggest that α-synuclein can spread in human brains and that it may even start in the peripheral nervous system, more specifically the enteric nervous system [4446]. This has led to the speculation that a pathogen, perhaps a virus or agent that could alter α-synuclein conformation, may initiate disease at the periphery and propagate back to the brain. The in vivo propagation of α-synuclein is also suggested by the presence of LB formation in fetal dopaminergic neurons that were transplanted in the striatum of PD patients as attempted therapeutic interventions [4749].

More recently, it was reported that intracerebral injection of extracts from sick A53T human α-synuclein trans genic mice (line M83) into younger healthy M83 transgenic mice could induce disease [50, 51]. The M83 transgenic mice normally develop a late-onset (8 to15 months of age) severe motor phenotype that leads to death and that results from the widespread formation of neuronal α-synuclein amyloidogenic inclusions [52]. The intracerebral injection of extracts from affected M83 mice resulted in an earlier presentation of both pathology and phenotype, and this induction was not observed in the younger mice injected with extracts generated from healthy mice [50, 51]. Furthermore, brain injection of preformed recombinant α-synuclein fibrils can induce α-synuclein pathology that appears to spread from the injection site [50], suggesting that these α-synuclein species can initiate and perhaps lead to transmission of α-synuclein pathology. Nevertheless, it is also possible that the observed induced pathology from both types of injections could be the result of a focal brain insult that initiates alternatively proposed pathological cascades such as oxidative stress, excitotoxicity, and neuroinflammation [53] that could result in similar observations.

Is the apparent spread of α-synuclein due solely to intra- and intercellular templating of α-synuclein aggregation?

Although many lines of evidence support the notion that α-synuclein may propagate in vivo via a prion-like mechanism, several findings are not completely consistent with this model. For example, pathological assessment of A53T (line M83) and E46K (line M47) human α-synuclein transgenic mice demonstrated that α-synuclein inclusion formation in these mice is late-onset, relatively rapid, and likely synchronized, but there is a paucity of neuronal inclusion clustering that is inconsistent with a spreading mechanism [54].

Although Lewy pathology was observed in some transplanted cells of several PD patients who received fetal mesencephalic grafts [4749], this phenomenon was observed in only a minority of these patients, even though some patients without Lewy pathology in grafted cells survived for a similar period of time following the transplant surgery [47, 53, 55]. It is possible that transmission is a very slow or inefficient process or, as noted above, that other alternative mechanisms may also lead to the observed induction of Lewy pathology in the transplanted cells [53]. Furthermore, extensive reviews of large cohorts of autopsied patients with PD/DLB have revealed that, for a significant percentage of patients, the distribution of α-synuclein pathology is not consistent with the Braak scheme of α-synuclein neuronal pathology spread [5658].

Moreover, the progression of pathology via a prion-like mechanism is not consistent with what is observed in multiple system atrophy (MSA). MSA is an adult-onset neurodegenerative disease that is characterized by varying degrees of parkinsonian features, cerebellar ataxia, and autonomic dysfunction [5961] but that is defined pathologically by the presence of glial cytoplasmic inclusions (GCIs) [62]. GCIs usually appear as flame or sickle inclusions in oligodendrocytes found throughout the white matter, but the greatest abundance of these inclusions occurs in the basal ganglia, the substantia nigra, the pontine nucleus, medulla, and cerebellum [6365]. Like Lewy pathology, GCIs are comprised predominantly of polymerized amyloidogenic α-synuclein [63, 66, 67]. Whereas most pathological inclusions in MSA are in oligodendrocytes, some α-synuclein protein aggregates can also be observed in the form of neuronal cytoplasmic inclusions, most of which are indistinguishable from LBs, and in neuritic processes, especially in the pontine nuclei and striatum [65, 68, 69]. α-Synuclein is expressed predominantly in neurons where it is localized to presynaptic terminals [7072] and is expressed only at very low levels or levels below detectability in oligodendrocytes [73, 74], and its expression is not increased in MSA [63, 66, 73]. Therefore, it is unclear why oligodendrocytes are affected predominantly in MSA. More importantly, if a prion-like mechanism is the primary mechanism for the spread of α-synuclein pathology, why is it confined predominantly to cells that express low levels of α-synuclein in MSA? Why does it not efficiently transmit to neurons? One possible mechanism that has been suggested to contribute to the spread of α-synuclein pathology is the release of amyloidogenic α-synuclein from dying cells. In MSA brains, 'ghost' GCIs where the cells have died are a common observation, suggesting that amyloidogenic α-synuclein from these cells should be readily available for the seeding in other neighboring cells.


Despite mounting evidence that a prion-like mechanism may contribute to the spread/progression of α-synuclein pathology in PD and DLB, several inconsistencies or alternative explanations [53, 75] for the observed experimental findings indicate that the pathogenic landscape is complex. Further experimental studies are needed to determine the relative importance and involvement of various pathogenic mechanisms, including self-templating resulting in altered protein conformation, neuroinflammation, oxidative stress, and excitotoxicity, in the apparent spread of α-synuclein pathology. This is especially important since extracellalar α-synuclein aggregates that would likely be involved in a prion-like spread of disease could lead to the design of novel therapeutic interventions such as conformation-specific monocloncal antibody therapy and regulation of specific extracellular proteases. The validity of pursuing this target will require a clearer understanding of both the pathological findings and experimental paradigms that point in this direction. Nevertheless, the possibility of preventing PD/DLB disease progression by blocking brain prion-like amyloid spread is an attractive hypothesis.



dementia with Lewy bodies


glial cytoplasmic inclusion


Lewy body


Lewy neurite


multiple system atrophy


Parkinson's disease


substantia nigra pars compacta.


  1. 1.

    Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology. 1967, 17: 427-442. 10.1212/WNL.17.5.427.

    CAS  Article  Google Scholar 

  2. 2.

    Simuni T, Hurtig HI: Parkinson's disease: the clinical picture. Neurodegenerative Dementias. Edited by: Clark CM, Trojanoswki JQ. 2000, New York: McGraw-Hill, 14: 193-203.

    Google Scholar 

  3. 3.

    Damier P, Hirsch EC, Agid Y, Graybiel AM: The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain. 1999, 122 (Pt 8): 1437-1448.

    Article  Google Scholar 

  4. 4.

    Pakkenberg B, Moller A, Gundersen HJ, Mouritzen DA, Pakkenberg H: The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry. 1991, 54: 30-33. 10.1136/jnnp.54.1.30.

    CAS  PubMed Central  Article  Google Scholar 

  5. 5.

    Lang AE, Lozano AM: Parkinson's disease. First of two parts. N Engl J Med. 1998, 339: 1044-1053. 10.1056/NEJM199810083391506.

    CAS  Article  Google Scholar 

  6. 6.

    Lang AE, Lozano AM: Parkinson's disease. Second of two parts. N Engl J Med. 1998, 339: 1130-1143. 10.1056/NEJM199810153391607.

    CAS  Article  Google Scholar 

  7. 7.

    McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB):report of the consortium on DLB international workshop. Neurology. 1996, 47: 1113-1124. 10.1212/WNL.47.5.1113.

    CAS  Article  Google Scholar 

  8. 8.

    Erro ME, Moreno MP, Zandio B: Pathophysiological bases of the non-motor symptoms in Parkinson's disease. Rev Neurol. 2010, 50 (Suppl 2): S7-13.

    Google Scholar 

  9. 9.

    Dickson DW, Fujishiro H, Orr C, DelleDonne A, Josephs KA, Frigerio R, Burnett M, Parisi JE, Klos KJ, Ahlskog JE: Neuropathology of non-motor features of Parkinson disease. Parkinsonism Relat Disord. 2009, 15 (Suppl 3): S1-S5.

    Article  Google Scholar 

  10. 10.

    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E: Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003, 24: 197-211. 10.1016/S0197-4580(02)00065-9.

    Article  Google Scholar 

  11. 11.

    Braak H, Braak E: Pathoanatomy of Parkinson's disease. J Neurol. 2000, 247 (Suppl 2): II3-10.

    Google Scholar 

  12. 12.

    Goedert M: Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001, 2: 492-501. 10.1038/35081564.

    CAS  Article  Google Scholar 

  13. 13.

    Waxman EA, Giasson BI: Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta. 2008, 1792: 616-624.

    PubMed Central  Article  Google Scholar 

  14. 14.

    Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature. 1997, 388: 839-840. 10.1038/42166.

    CAS  Article  Google Scholar 

  15. 15.

    Cushman M, Johnson BS, King OD, Gitler AD, Shorter J: Prion-like disorders: blurring the divide between transmissibility and infectivity. J Cell Sci. 2010, 123: 1191-1201. 10.1242/jcs.051672.

    CAS  PubMed Central  Article  Google Scholar 

  16. 16.

    Martin I, Dawson VL, Dawson TM: Recent advances in the genetics of Parkinson's disease. Annu Rev Genomics Hum Genet. 2011, 12: 301-325. 10.1146/annurev-genom-082410-101440.

    CAS  PubMed Central  Article  Google Scholar 

  17. 17.

    Lesage S, Brice A: Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009, 18: R48-R59. 10.1093/hmg/ddp012.

    CAS  Article  Google Scholar 

  18. 18.

    Westerlund M, Hoffer B, Olson L: Parkinson's disease: Exit toxins, enter genetics. Prog Neurobiol. 2010, 90: 146-156. 10.1016/j.pneurobio.2009.11.001.

    CAS  PubMed Central  Article  Google Scholar 

  19. 19.

    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997, 276: 2045-2047. 10.1126/science.276.5321.2045.

    CAS  Article  Google Scholar 

  20. 20.

    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O: Ala30Pro mutation in the gene encoding alphasynuclein in Parkinson's disease. Nat Genet. 1998, 18: 106-108. 10.1038/ng0298-106.

    CAS  Article  Google Scholar 

  21. 21.

    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez TE, del Ser T, Munoz DG, de Yebenes JG: The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004, 55: 164-173. 10.1002/ana.10795.

    CAS  Article  Google Scholar 

  22. 22.

    Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW: Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol. 2004, 55: 174-179. 10.1002/ana.10846.

    CAS  Article  Google Scholar 

  23. 23.

    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K: alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003, 302: 841-10.1126/science.1090278.

    CAS  Article  Google Scholar 

  24. 24.

    Goldberg MS, Lansbury PT: Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson's disease?. Nat Cell Biol. 2000, 2: E115-E119. 10.1038/35017124.

    CAS  Article  Google Scholar 

  25. 25.

    Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ: Synuclein activates microglia in a model of Parkinson's disease. Neurobiol Aging. 2008, 29: 1690-1701. 10.1016/j.neurobiolaging.2007.04.006.

    CAS  PubMed Central  Article  Google Scholar 

  26. 26.

    Lee HJ, Patel S, Lee SJ: Intravesicular localization and exocytosis of alphasynuclein and its aggregates. J Neurosci. 2005, 25: 6016-6024. 10.1523/JNEUROSCI.0692-05.2005.

    CAS  Article  Google Scholar 

  27. 27.

    El-Agnaf OM, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ, Curran MD, Court JA, Mann DM, Ikeda S, Cookson MR, Hardy J, Allsop D: Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003, 17: 1945-1947.

    CAS  Google Scholar 

  28. 28.

    El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D: Detection of oligomeric forms of alphasynuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 2006, 20: 419-425. 10.1096/fj.03-1449com.

    CAS  Article  Google Scholar 

  29. 29.

    Borghi R, Marchese R, Negro A, Marinelli L, Forloni G, Zaccheo D, Abbruzzese G, Tabaton M: Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci Lett. 2000, 287: 65-67. 10.1016/S0304-3940(00)01153-8.

    CAS  Article  Google Scholar 

  30. 30.

    Emmanouilidou E, Elenis D, Papasilekas T, Stranjalis G, Gerozissis K, Ioannou PC, Vekrellis K: Assessment of alpha-synuclein secretion in mouse and human brain parenchyma. PLoS One. 2011, 6: e22225-10.1371/journal.pone.0022225.

    CAS  PubMed Central  Article  Google Scholar 

  31. 31.

    Ahn KJ, Paik SR, Chung KC, Kim J: Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein. J Neurochem. 2006, 97: 265-279. 10.1111/j.1471-4159.2006.03731.x.

    CAS  Article  Google Scholar 

  32. 32.

    Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ: Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol. 2008, 40: 1835-1849. 10.1016/j.biocel.2008.01.017.

    CAS  Article  Google Scholar 

  33. 33.

    Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA. 2009, 106: 13010-13015. 10.1073/pnas.0903691106.

    CAS  PubMed Central  Article  Google Scholar 

  34. 34.

    Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K: Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010, 30: 6838-6851. 10.1523/JNEUROSCI.5699-09.2010.

    CAS  PubMed Central  Article  Google Scholar 

  35. 35.

    Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P: alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011, 121: 715-725. 10.1172/JCI43366.

    CAS  PubMed Central  Article  Google Scholar 

  36. 36.

    Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ: Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010, 285: 9262-9272. 10.1074/jbc.M109.081125.

    CAS  PubMed Central  Article  Google Scholar 

  37. 37.

    Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M: Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J Biol Chem. 1999, 274: 9843-9846. 10.1074/jbc.274.14.9843.

    CAS  Article  Google Scholar 

  38. 38.

    Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL: alphasynuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. J Biol Chem. 1999, 274: 19509-19512. 10.1074/jbc.274.28.19509.

    CAS  Article  Google Scholar 

  39. 39.

    Waxman EA, Giasson BI: A novel, high-efficiency cellular model of fibrillar alpha-synuclein inclusions and the examination of mutations that inhibit amyloid formation. J Neurochem. 2010, 113: 374-388. 10.1111/j.1471-4159.2010.06592.x.

    CAS  PubMed Central  Article  Google Scholar 

  40. 40.

    Luk KC, Song C, O'Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ: Lee Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci USA. 2009, 106: 20051-20056.

    CAS  PubMed Central  Article  Google Scholar 

  41. 41.

    Nonaka T, Hasegawa : Seeded aggregation and toxicity of alpha-synuclein and tau: cellular models of neurodegenerative diseases. J Biol Chem. 2010, 285: 34885-34898. 10.1074/jbc.M110.148460.

    CAS  PubMed Central  Article  Google Scholar 

  42. 42.

    Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM: Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011, 72: 57-71. 10.1016/j.neuron.2011.08.033.

    CAS  PubMed Central  Article  Google Scholar 

  43. 43.

    Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del TK: Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord. 2006, 21: 2042-2051. 10.1002/mds.21065.

    Article  Google Scholar 

  44. 44.

    Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F: Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses. Acta Neuropathol. 1988, 76: 217-221. 10.1007/BF00687767.

    CAS  Article  Google Scholar 

  45. 45.

    Braak H, de Vos RA, Bohl J, Del TK: Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. 2006, 396: 67-72. 10.1016/j.neulet.2005.11.012.

    CAS  Article  Google Scholar 

  46. 46.

    Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama B: Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol. 2003, 62: 644-654.

    CAS  Article  Google Scholar 

  47. 47.

    Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008, 14: 504-506. 10.1038/nm1747.

    CAS  Article  Google Scholar 

  48. 48.

    Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P: Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008, 14: 501-503. 10.1038/nm1746.

    CAS  Article  Google Scholar 

  49. 49.

    Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O, Brundin P: Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov Disord. 2010, 25: 1091-1096. 10.1002/mds.23012.

    Article  Google Scholar 

  50. 50.

    Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, Lee VM: Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med. 2012, 209: 975-986. 10.1084/jem.20112457.

    CAS  PubMed Central  Article  Google Scholar 

  51. 51.

    Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L, Legastelois S, Baron T: Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. 2012, 33: 2225-2228. 10.1016/j.neurobiolaging.2011.06.022.

    CAS  Article  Google Scholar 

  52. 52.

    Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM: Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron. 2002, 34: 521-533. 10.1016/S0896-6273(02)00682-7.

    CAS  Article  Google Scholar 

  53. 53.

    Brundin P, Li JY, Holton JL, Lindvall O, Revesz T: Research in motion: the enigma of Parkinson's disease pathology spread. Nat Rev Neurosci. 2008, 9: 741-745.

    CAS  Article  Google Scholar 

  54. 54.

    Emmer KL, Waxman EA, Covy JP, Giasson BI: E46K human alpha-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J Biol Chem. 2011, 286: 35104-35118. 10.1074/jbc.M111.247965.

    CAS  PubMed Central  Article  Google Scholar 

  55. 55.

    Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O: Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med. 2008, 14: 507-509. 10.1038/nm1752.

    CAS  PubMed Central  Article  Google Scholar 

  56. 56.

    Jellinger KA: A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta. 2009, 1792: 730-740. 10.1016/j.bbadis.2008.07.006.

    CAS  Article  Google Scholar 

  57. 57.

    Burke RE, Dauer WT, Vonsattel JP: A critical evaluation of the Braak staging scheme for Parkinson's disease. Ann Neurol. 2008, 64: 485-491. 10.1002/ana.21541.

    PubMed Central  Article  Google Scholar 

  58. 58.

    Frigerio R, Fujishiro H, Ahn TB, Josephs KA, Maraganore DM, DelleDonne A, Parisi JE, Klos KJ, Boeve BF, Dickson DW, Ahlskog JE: Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies?. Neurobiol Aging. 2011, 32: 857-863. 10.1016/j.neurobiolaging.2009.05.019.

    CAS  PubMed Central  Article  Google Scholar 

  59. 59.

    Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP: Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain. 1994, 117 (Pt 4): 835-845.

    Article  Google Scholar 

  60. 60.

    Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP: Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 1997, 12: 133-147. 10.1002/mds.870120203.

    CAS  Article  Google Scholar 

  61. 61.

    Gilman S, Low PA, Quinn N, Albanese A, Ben Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK: Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999, 163: 94-98. 10.1016/S0022-510X(98)00304-9.

    CAS  Article  Google Scholar 

  62. 62.

    Papp MI, Kahn JE, Lantos PL: Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. 1989, 94: 79-100. 10.1016/0022-510X(89)90219-0.

    CAS  Article  Google Scholar 

  63. 63.

    Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB, Gollomp SM, Grossman M, Lee VMY, Trojanowski JQ: Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol. 2000, 59: 830-841.

    CAS  Article  Google Scholar 

  64. 64.

    Lantos PL: Mutliple system atrophy. Brain Pathol. 1997, 7: 1293-1297.

    CAS  Article  Google Scholar 

  65. 65.

    Arima K, Murayama S, Mukoyama M, Inose T: Immunocytochemical and ultrastructural studies of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. 1. Neuronal cytoplasmic inclusions. Acta Neuropathol (Berl). 1992, 83: 453-460. 10.1007/BF00310020.

    CAS  Article  Google Scholar 

  66. 66.

    Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VMY: Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 1998, 44: 415-422. 10.1002/ana.410440324.

    CAS  Article  Google Scholar 

  67. 67.

    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett. 1998, 251: 205-208. 10.1016/S0304-3940(98)00504-7.

    CAS  Article  Google Scholar 

  68. 68.

    Arima K, Ueda K, Sunohara N, Arakawa K, Hirai S, Nakamura M, Tonozuka-Uehara H, Kawai M: NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol (Berl). 1998, 96: 439-444. 10.1007/s004010050917.

    CAS  Article  Google Scholar 

  69. 69.

    Kato S, Nakamura H: Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies. Acta Neuropathol (Berl). 1990, 79: 584-594. 10.1007/BF00294235.

    CAS  Article  Google Scholar 

  70. 70.

    Jakes R, Spillantini MG, Goedert M: Identification of two distinct synucleins from human brain. FEBS Lett. 1994, 345: 27-32. 10.1016/0014-5793(94)00395-5.

    CAS  Article  Google Scholar 

  71. 71.

    Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T: The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995, 14: 467-475. 10.1016/0896-6273(95)90302-X.

    CAS  Article  Google Scholar 

  72. 72.

    Maroteaux L, Campanelli JT, Scheller RH: Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988, 8: 2804-2815.

    CAS  Google Scholar 

  73. 73.

    Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB: Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm. 2005, 112: 1613-1624. 10.1007/s00702-005-0378-1.

    CAS  Article  Google Scholar 

  74. 74.

    George JM, Jin H, Woods WS, Clayton DF: Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron. 1995, 15: 361-372. 10.1016/0896-6273(95)90040-3.

    CAS  Article  Google Scholar 

  75. 75.

    Lema Tomé CM, Tyson T, Rey NL, Grathwohl S, Britschgi M, Brundin P: Inflammation and alpha-synuclein's prion-like behavior in Parkinson's disease-Is there a link?. Mol Neurobiol. 2012,

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Benoit I Giasson.

Additional information

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sacino, A.N., Giasson, B.I. Does a prion-like mechanism play a major role in the apparent spread of α-synuclein pathology?. Alz Res Therapy 4, 48 (2012).

Download citation

  • Published:

  • DOI:


  • Multiple System Atrophy
  • Neuronal Cytoplasmic Inclusion
  • Lewy Pathology
  • Multiple System Atrophy Brain
  • Apparent Spread