LAUSR

Significance Huntington’s disease is a fatal neurodegenerative condition caused by polyglutamine expansion (≥35) in the N-terminal region of the huntingtin protein encoded by exon-1 (httex1), resulting in fibril accumulation within neuronal inclusion bodies. Microsecond-timescale reversible oligomerization to generate sparsely populated tetramers of the N-terminal amphiphilic domain of httex1 is critical for nucleation and elongation on the hours timescale to form fibrils comprising a polyglutamine core. Here, we develop an NMR approach to simultaneously quantify the kinetics of transient tetramerization and irreversible fibril formation of a pathogenic httex1 construct with 35 glutamines. Native httex1 undergoes tetramer-dependent primary nucleation and monomer-dependent elongation and secondary nucleation, whereas the Met7 sulfoxide form, which does not tetramerize or nucleate, is still incorporated into fibrils via elongation.