α-synuclein is a synaptic protein found in aggregates (Lewy bodies) in Parkinson's disease and dementia with Lewy bodies. It is also found as inclusions in the neuroglial in multiple system atrophy and in other abnormal disposition in several other neurodegenerative diseases of the central nervous system. It has recently been postulated that presynaptic alpha-synuclein aggregates may actually be the common association. Further it seems a functional gut biome (bacterial colonisation) may be necessary to induce the neuropathology. Accumulation of alpha-synuclein in cultured human dopaminergic neurons exposed to dopamine and oxygen radicals results in apoptosis. Alpha-synuclein is not toxic in nondopaminergic human cortical neurons. An 11 amino acid core (NACore) appears to be responsible for the abnormal toxic amyloid deposition and these deposits can be too small to be seen on optical microscopy.
Mutations of alpha-synuclein gene (SNCA) at 4q21 cause some familial Parkinson's disease:
- PARK1 (OMIM:168601) - various point mutations eg ala53-to-thr (A53T), ala30-to-pro (A30P) substitution and SNCA duplication.
- PARK4 (OMIM:605543) - triplication
- Autosomal dominant Lewy body dementia (OMIM:127750)- glu46-to-lys (E46K) mutation
- ↑ Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27:1405-10. (Direct link – subscription may be required.)
- ↑ Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec; 167(6):1469-1480.e12.(Print) (Link to article – subscription may be required.)
- ↑ Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nature medicine 2002;8:600-6. (Direct link – subscription may be required.)
- ↑ Rodriguez JA, Ivanova MI, Sawaya MR, Cascio D, Reyes FE, Shi D, Sangwan S, Guenther EL, Johnson LM, Zhang M, Jiang L, Arbing MA, Nannenga BL, Hattne J, Whitelegge J, Brewster AS, Messerschmidt M, Boutet S, Sauter NK, Gonen T, Eisenberg DS. Structure of the toxic core of α-synuclein from invisible crystals. Nature. 2015 Sep 9.(Epub ahead of print) (Link to article – subscription may be required.)