By Tom Fagan
Dense protein aggregates formed from misfolded protein monomers are a feature of many neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases, amyotrophic lateral sclerosis (ALS), and prion diseases, such as Creutzfeldt-Jakob disease. Protein aggregation is also a facet of non-neurodegenerative diseases, such as systemic amyloid A amyloidosis. Of all these disorders, the prion diseases are unique because pathogenic prion proteins are infectious agents that seed the misfolding of normal prion protein and its subsequent aggregation in normal cells and organisms. Different protein conformations, or strains, of prions can also cause disease characteristics or phenotypes (Collinge et al., 2007).
But are prions truly unique in this? A flurry of recent research suggests otherwise. Though misfolded amyloidβ (Aβ), α-synuclein, huntingtin, and other aggregation-prone proteins may not be infectious agents in the sense that they spread disease from one person to the next, evidence has grown that within an individual organism, misfolded forms of these proteins spread through cells and tissues, corrupting normal proteins and seeding protein aggregation as they go. If this is a common mechanism for the spread of pathogenic proteins in a given person, it would have profound implications for the study and treatment of neurodegenerative diseases.
Early evidence that non-prion proteins may seed protein aggregation in vivo came from Lary Walker’s lab at Emory University, Atlanta, Georgia. Walker and colleagues showed that Alzheimer disease brain extracts infused into young APP mice could precipitate protein aggregation five months later (Kane et al., 2001). In primates, too, seeding with Aβ-laden brain extracts increases the likelihood that amyloid plaques will develop with age (Ridley et al., 2006).
More recently, Mathias Jucker, Hertie Institute for Clinical Brain Research in Tubingen, Germany, and colleagues showed that when injected into discrete locations in the brain of young APP23 mice, diluted extracts from aged APP23 transgenic mice can induce plaque formation near the injection site within three months, and that the pathology spreads to more distal regions by six months (see ARF news on Eisele et al., 2009). The finding supports the idea that Aβ seeds can diffuse and corrupt normal protein in the brain. Earlier, Jucker and colleagues also reported that the type of plaque induced by brain extracts depends not only the type of Aβ in the extract, but also on the nature of the Aβ in the host. Extracts from APP/PS1 transgenic mice produce coarser, more punctate Aβ deposits in APP23 mice, whereas extracts from APP23 mice cause more diffuse plaques in these animals. These phenotypes may depend on the relative amounts of Aβ40 and Aβ42 in the donors and hosts. This would seem to support the idea that, like with prions, there can be different “strains” of Aβ (see ARF related news on Meyer-Luehmann et al., 2006). Fluctuating Aβ40/42 ratios may even be linked to regional brain differences in plaque morphology.
This year, strong evidence for the seeding and propagation of the microtubule protein tau also emerged. At the cellular level, Marc Diamond, now at Washington University, St. Louis, Missouri, and colleagues showed that tau, even though it is an intracellular protein, forms seeds that can be passed from one cell to the next, where the seeds induce aggregation of normal tau (see ARF related news on Frost et al., 2009). Tau seeding also occurs in vivo, according to work from the labs of Markus Tolnay at the University of Basel, Switzerland and Michel Goedert MRC Laboratory of Molecular Biology, Cambridge, UK. They showed that brain extracts from P301S tau transgenic mice, which produce filamentous tau aggregates, can induce tau aggregation in another tau-overexpressing mouse strain (ALZ17 mice) that do not normally make tau filaments. Tau aggregates in the ALZ17 mice took six months to appear, and they grew further over the next 6 – 8 months. Importantly, the aggregates spread from the injection site to connected sites in the brain, hinting that the spread of tau pathology in human disease may follow neuronal circuits. Interestingly, Diamond’s work suggests that tau, too, occurs in at least two conformations, or strains, that differ in secondary structure. Seeding with mutant tau drives wild-type (WT) tau into a secondary structure that Diamond calls WT*.
Huntingtin and α-synuclein
The prion-like creep of protein aggregates in the brain is not limited to Alzheimer disease. Mutant huntingtin and α-synuclein may spread in a similar fashion in Huntington and Parkinson diseases, respectively. Ron Kopito’s lab at Stanford University, California, showed that huntingtin-like protein fragments with expanded polyglutamine stretches (Q44) can gain entry into cells and seed aggregation of normal-length (Q25) peptides (see ARF news and Ren et al., 2009). The spread and induction of α-synuclein from one cell to another in vitro was recently described by researchers led by Seung-Jae Lee, Konkuk University in Seoul, South Korea and by Eliezer Masliah, University of California at San Diego (see related ARF news on Desplats et al., 2009). These investigators further showed that normal stem cells transplanted into mutant α-synuclein transgenic mice also acquired the mutant protein, suggesting that cell-to-cell transfer occurs in vivo. This experiment might help explain why normal cell grafts transplanted into the brain of Parkinson’s patients succumbed to Parkinson pathology years later (see related ARF news).
Outside the brain, prion-like mechanisms are known to occur, for example, in systemic amyloidoses. Amyloid A (AA) fibrils can induce AA aggregation when injected into mice (see Lundmark et al., 2002), as can fibrils of apolipoprotein AII (see Xing et al., 2001).
Selected Reviews on Seeding of Proteopathy:
Aguzzi A, Baumann F, Bremer J. The prion's elusive reason for being. Annu Rev Neurosci. 2008;31:439-77. Abstract
Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007 Nov 9;318(5852):930-6. Abstract
Frost B, Diamond MI. The expanding realm of prion phenomena in neurodegenerative disease. Prion. 2009 Apr;3(2):74-7. Abstract
Lansbury PT. Structural neurology: are seeds at the root of neuronal degeneration? Neuron. 1997 Dec;19(6):1151-4.
Sigurdsson EM, Wisniewski T, Frangione B. Infectivity of amyloid diseases. Trends Mol Med. 2002 Sep;8(9):411-3. Abstract
Soto C, Estrada L, Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci. 2006 Mar;31(3):150-5. Abstract
Walker LC, Levine H, Mattson MP, Jucker M. Inducible proteopathies. Trends Neurosci. 2006 Aug;29(8):438-43. Abstract
Selected Primary Papers on Seeding:
Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am J Pathol. 2007 Dec;171(6):2012-20. Abstract
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. Abstract
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 U S A. 2009 Aug 4;106(31):13010-5. Abstract
Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. Abstract
Fu X, Korenaga T, Fu L, Xing Y, Guo Z, Matsushita T, Hosokawa M, Naiki H, Baba S, Kawata Y, Ikeda S, Ishihara T, Mori M, Higuchi K. Induction of AApoAII amyloidosis by various heterogeneous amyloid fibrils. FEBS Lett. 2004 Apr 9;563(1-3):179-84. Abstract
Gaspar RC, Villarreal SA, Bowles N, Hepler RW, Joyce JG, Shughrue PJ. Oligomers of beta-amyloid are sequestered into and seed plaques in the brains of an AD mouse model. Exp Neurol. 2009 Sep 8; Abstract
Götz J, Chen F, Van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24;293(5534):1491-5. Abstract
Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, Roher AE, Walker LC. Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice. J Neurosci. 2000 May 15;20(10):3606-11. Abstract
Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, Dearmond SJ, Prusiner SB. Synthetic mammalian prions. Science. 2004 Jul 30;305(5684):673-6. Abstract
Lundmark K, Westermark GT, Nyström S, Murphy CL, Solomon A, Westermark P. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6979-84. Abstract
Lundmark K, Westermark GT, Olsén A, Westermark P. Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6098-102. Abstract
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. Abstract
Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science. 2005 Jan 14;307(5707):262-5. Abstract
Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009 Feb;11(2):219-25. Abstract
Ridley RM, Baker HF, Windle CP, Cummings RM. Very long term studies of the seeding of beta-amyloidosis in primates. J Neural Transm. 2006 Sep;113(9):1243-51. Abstract
Solomon A, Richey T, Murphy CL, Weiss DT, Wall JS, Westermark GT, Westermark P. Amyloidogenic potential of foie gras. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10998-1001. Abstract
Vande Velde C, Miller TM, Cashman NR, Cleveland DW. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):4022-7. Abstract
Westermark P, Lundmark K, Westermark GT. Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model. PLoS One. 2009;4(6):e6041.Abstract
Xing 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 Apr;81(4):493-9. Abstract
Zhang 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 U S A. 2008 May 20;105(20):7263-8. Abstract
Zhou Z, Fan JB, Zhu HL, Shewmaker F, Yan X, Chen X, Chen J, Xiao GF, Guo L, Liang Y. Crowded, Cell-like Environment Accelerates the Nucleation Step of Amyloidogenic Protein Misfolding. J Biol Chem. 2009 Sep 10; Abstract