Biology: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
Alpha-synuclein 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
- ↑ "Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease". Biochemistry 42 (26): 7871–8. 2003. doi:10.1021/bi030086j. PMID 12834338.
- ↑ "Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease". Nature Medicine 4 (11): 1318–20. November 1998. doi:10.1038/3311. PMID 9809558.
- ↑ "Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein". Neuron 34 (4): 521–33. 2002. doi:10.1016/S0896-6273(02)00682-7. PMID 12062037.
- ↑ "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. 2003. doi:10.1016/S1044-7431(03)00198-2. PMID 14572463.
- ↑ "Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death". The Journal of Neuroscience 26 (1): 41–50. 2006. doi:10.1523/JNEUROSCI.4308-05.2006. PMID 16399671.
- ↑ 6.0 6.1 "Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils". Journal of Molecular Biology 322 (5): 1089–102. 2002. doi:10.1016/S0022-2836(02)00735-0. PMID 12367530. http://infoscience.epfl.ch/record/142131.
- ↑ "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. 2002. doi:10.1074/jbc.M208192200. PMID 12351642.
- ↑ "Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct". Science 294 (5545): 1346–9. 2001. doi:10.1126/science.1063522. PMID 11701929.
- ↑ "Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease". Biochemistry 40 (26): 7812–9. 2001. doi:10.1021/bi0102398. PMID 11425308.
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