Aggregation and properties of α‒synuclein and related proteins

α-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms have been associated with early onset Parkinson's disease. A fragment of α-synuclein has also been identified as the non-A β component of Alzheimer's disease amyloid (NAC). Ageing solutions of α-synuclein and NAC leads to formation of β-sheet, detectable by circular dichroism spectroscopy, and aggregation to form amyloid-like fibrils, detectable by electron microscopy. Differences in the rates of aggregation of the fibrils formed by α-synuclein and the two mutant proteins are presented. The toxicity of α-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identi- fied. Synucleins are a family of small proteins (127-140 amino acid residues for the human forms) ex- pressed at highest levels in nervous tissue. Three members, α-, β-, and γ-synucleins, are the products of three genes present on three different chromosomes (10). A fourth member, synoretin, is expressed most highly in retina (49). The first indication of an involvement of α-synuclein in the pathogenesis of neu- rodegenerative diseases came from the isolation, from purified amyloid of Alzheimer's disease brains, of a novel peptide unrelated to Aβ. This peptide, representing about 10% of the non-SDS soluble material, was named non-Aβ-component of Alzheimer's disease amyloid (NAC). Sequencing revealed that NAC comprised at least 35 amino acids, although the N-terminal residues could not be assigned with certainty because of the specificity of the enzyme used in sequencing (53). These 35 amino acids correspond to residues 61-95 of a 140 amino-acid precursor (NACP), later shown to be identical to α-synuclein. Inter- est in α-synuclein was enormously enhanced when two different mutations in the α-synuclein gene were found in inherited forms of Parkinson's disease. One mutation, α-synuclein(A53T), found in certain Ital- ian and Greek families, results in an Ala 53 to Thr substitution in a region predicted to adopt an α-helical structure surrounded by β-sheets (42). The other mutation, α-synuclein(A30P), an Ala 30 to Pro change, was detected in a family of German origin (32). It has been suggested that these amino acid substitutions