If alpha-synuclein has a pathogenic hotspot, residues 41 to 60 is it. Within this single twenty-residue stretch sit the sites of E46K, H50Q, G51D and A53T, and the segment runs up to the boundary of the hydrophobic NAC region beginning near residue 61. A53T was the first SNCA mutation associated with familial Parkinson's disease. More striking is that G51D, two positions away, has been linked to a phenotype overlapping multiple system atrophy rather than classical Parkinson's, so substitutions separated by a couple of residues can produce clinically distinguishable disease. That sensitivity is what makes the window interesting to work on and difficult to generalise about. Its position at the domain junction gives a second use. Compared against a peptide extending further into the hydrophobic core, it separates binding that depends on the mutation-dense N-terminal stretch from binding that requires the aggregation segment beyond it — a distinction that full-length protein cannot resolve, since both regions are present. | 