A53T Mutation

A53T Mutation is a point mutation of the Alpha-synuclein protein, a 140-amino acid protein found in pre-synaptic terminals of neurons in the brain.

Protein

This protein has more than one known point-mutation, one being A53T where amino acid residue 53 is mutated from its native alanine to a threonine.[1] Wild-type alpha-synuclein fibrils are known to be the primary component of Lewy bodies, which are found in the brain of Parkinson's disease patients. The A53T mutation has been shown have faster kinetics of fibrilization than the wild-type protein. A53T alpha-synuclein has also been linked to early on-set familial Parkinson's disease.[2] Advancements in technology have allowed the development of transgenic mice expressing A53T alpha-synuclein that have been used in multiple studies on Parkinson's disease.[3][4][5] Wild-type alpha-synuclein has been shown to form oligomeric species termed protofibrils before forming full fibrils. Research has been conducted to test the hypothesis that the oligomeric protofibril species is neurotoxic rather than the fibrillar species.[6][7][8] Electron microscopy has revealed that the A53T mutant protein formed annular and tubular protofibrils easily, whereas the wild-type protein formed annular protofibrils only after extended incubation.[6] This early on-set mutation has been shown to increase the protofibril population that, if toxic, would increase the amount of the toxic species in the brain.[9] There is clinical significance in studying the effects of A53T alpha-synuclein on the protofibrillar species as it may be a relevant therapeutic target in treating early on-set Parkinson's disease.

References
  1. Volles MJ, Lansbury PT (2003). "Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease". Biochemistry. 42 (26): 7871–8. doi:10.1021/bi030086j. PMID 12834338.
  2. Conway KA, Harper JD, Lansbury PT (November 1998). "Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease". Nature Medicine. 4 (11): 1318–20. doi:10.1038/3311. PMID 9809558.
  3. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002). "Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein". Neuron. 34 (4): 521–33. doi:10.1016/S0896-6273(02)00682-7. PMID 12062037.
  4. Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf HW, Deller T, Braak H, Auburger G, Nussbaum RL (2003). "Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation". Molecular and Cellular Neurosciences. 24 (2): 419–29. doi:10.1016/S1044-7431(03)00198-2. PMID 14572463.
  5. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006). "Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death". The Journal of Neuroscience. 26 (1): 41–50. doi:10.1523/JNEUROSCI.4308-05.2006. PMC 6381830. PMID 16399671.
  6. Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T, Lansbury PT (2002). "Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils". Journal of Molecular Biology. 322 (5): 1089–102. doi:10.1016/S0022-2836(02)00735-0. PMID 12367530.
  7. Lee HJ, Lee SJ (2002). "Characterization of cytoplasmic alpha-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells". The Journal of Biological Chemistry. 277 (50): 48976–83. doi:10.1074/jbc.M208192200. PMID 12351642.
  8. Conway KA, Rochet JC, Bieganski RM, Lansbury PT (2001). "Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct". Science. 294 (5545): 1346–9. doi:10.1126/science.1063522. PMID 11701929.
  9. Volles MJ, Lee SJ, Rochet JC, Shtilerman MD, Ding TT, Kessler JC, Lansbury PT (2001). "Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease". Biochemistry. 40 (26): 7812–9. doi:10.1021/bi0102398. PMID 11425308.
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