Huang Jinfeng, Ahmed Rashik, Akimoto Madoka, Martinez Pomier Karla, Melacini Giuseppe
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4M1, Canada.
JACS Au. 2023 Dec 13;3(12):3485-3493. doi: 10.1021/jacsau.3c00655. eCollection 2023 Dec 25.
Alpha synuclein (αS) aggregates are the main component of Lewy bodies (LBs) associated with Parkinson's disease (PD). A longstanding question about αS and PD pertains to the autosomal dominant E46K αS mutant, which leads to the early onset of PD and LB dementias. The E46K mutation not only promotes αS aggregation but also stabilizes αS monomers in "closed" conformers, which are compact and aggregation-incompetent. Hence, the mechanism of action of the E46K mutation is currently unclear. Here, we show that αS monomers harboring the E46K mutation exhibit more extensive interactions with fibrils compared to those of WT. Such monomer-fibril interactions are sufficient to allosterically drive transitions of αS monomers from closed to open conformations, enabling αS aggregation. We also show that E46K promotes head-to-tail monomer-monomer interactions in early self-association events. This multipronged mechanism provides a new framework to explain how the E46K mutation and possibly other αS variants trigger early-onset PD.
α-突触核蛋白（αS）聚集体是与帕金森病（PD）相关的路易小体（LB）的主要成分。一个关于αS和PD的长期问题涉及常染色体显性E46K αS突变体，该突变体会导致PD和LB痴呆的早发。E46K突变不仅促进αS聚集，还使αS单体稳定在“封闭”构象中，这种构象紧密且无聚集能力。因此，E46K突变的作用机制目前尚不清楚。在这里，我们表明，与野生型相比，携带E46K突变的αS单体与原纤维表现出更广泛的相互作用。这种单体-原纤维相互作用足以通过变构驱动αS单体从封闭构象转变为开放构象，从而使αS聚集。我们还表明，E46K在早期自组装事件中促进头对头单体-单体相互作用。这种多方面的机制为解释E46K突变以及可能的其他αS变体如何引发早发性PD提供了一个新框架。
