Alpha-synuclein: prion or prion-like?
Misfolded alpha-synuclein is a corruptive seed, but is it infectious?
Alpha-synuclein is a natively unfolded or intrinsically disordered protein, but it can also assume amphipathic alpha-helical shapes in the presence of negatively charged lipids. In Lewy body disorders, alpha-synuclein monomers aggregate into oligomers, protofibrils, and fibrils, forming part of the hallmark amyloid inclusions known as Lewy bodies and Lewy neurites. Proteins exist in biological settings in multiple conformations, often with varied biological functions, and the transitions between conformations include structures that seed the nucleated growth of aggregates . After the kinetic barrier to aggregation of natively monomeric proteins is (rarely) overcome, the global free-energy minimum favors the precipitation of hydrophobically packed protein masses . Once this low-energy state is acquired, it may not be energetically feasible to proteolyze and resolve the protein mass, and therefore, “the...
We apologize to those authors whose work we had no room to cite. This commentary was supported by National Institutes of Health (NIH) Grants 1R15NS093539 and 1R21NS107960 to Rehana Leak. Additional support was provided by NIH Grants P30AG062421 to Matthew Frosch, NIH Grants U24NS072026 and P30AG19610 to Thomas Beach, and National Health and Medical Research Council (NHMRC) Grant #1079679 to Senior Principal Research Fellow Glenda Halliday. The authors declare no conflicts of interest.
- 10.Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. https://doi.org/10.1146/annurev.biochem.75.101304.123901 CrossRefGoogle Scholar
- 12.Fares MB, Ait-Bouziad N, Dikiy I, Mbefo MK, Jovicic A, Kiely A et al (2014) The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet 23:4491–4509. https://doi.org/10.1093/hmg/ddu165 CrossRefGoogle Scholar
- 16.Haley NJ, Mathiason CK, Carver S, Zabel M, Telling GC, Hoover EA (2011) Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission. J Virol 85:6309–6318. https://doi.org/10.1128/JVI.00425-11 CrossRefGoogle Scholar
- 18.Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM et al (2013) Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 70:462–468. https://doi.org/10.1001/jamaneurol.2013.1933 CrossRefGoogle Scholar
- 23.Koch R, Pinner M, Pinner BR, National tuberculosis association (1932) The aetiology of tuberculosis. National tuberculosis association, SmyrnaGoogle Scholar
- 28.Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O et al (2010) Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov Disord 25:1091–1096. https://doi.org/10.1002/mds.23012 CrossRefGoogle Scholar
- 45.Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW et al (2014) Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci USA 111:10732–10737. https://doi.org/10.1073/pnas.1321785111 CrossRefGoogle Scholar