One ring is sufficient to inhibit α-synuclein aggregation

Parkinson's disease, the second most prevalent neurodegenerative disorder worldwide, is characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta, causing motor symptoms. This disorder's main hallmark is the formation of intraneuronal protein inclusions, named Lewy bodies and neurites. The major component of these arrangements is alpha -synuclein, an intrinsically disordered and soluble protein that, in pathological conditions, can form toxic and cell-to-cell transmissible amyloid structures. Preventing alpha -synuclein aggregation has attracted significant effort in the search for a disease-modifying therapy for Parkinson's disease. Small molecules like SynuClean-D, epigallocatechin gallate, trodusquemine, or anle138b exemplify this therapeutic potential. Here, we describe a subset of compounds containing a single aromatic ring, like dopamine, ZPDm, gallic acid, or entacapone, which act as molecular chaperones against alpha -synuclein aggregation. The simplicity of their structures contrasts with the complexity of the aggregation process, yet the block efficiently alpha -synuclein assembly into amyloid fibrils, in many cases, redirecting the reaction towards the formation of non-toxic off-pathway oligomers. Moreover, some of these compounds can disentangle mature alpha -synuclein amyloid fibrils. Their simple structures allow structure-activity relationship analysis to elucidate the role of different functional groups in the inhibition of alpha -synuclein aggregation and fibril dismantling, making them informative lead scaffolds for the rational development of efficient drugs.

Automated summary

Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide, characterized by the loss of dopaminergic neurons and the abnormal aggregation of alpha-synuclein. Some compounds with a single aromatic ring can act as molecular chaperones to inhibit alpha-synuclein aggregation and promote the formation of non-toxic oligomers.