Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease

Abstract

The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson’s and Alzheimer’s diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson’s disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson’s disease and related conditions.

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

“…1A), an intrinsically disordered protein expressed at high levels in the brain, is closely associated with the pathogenesis of a variety of neurodegenerative disorders, collectively known as α-synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA) (1)(2)(3)(4)(5)(6)(7). It has been exceptionally challenging, however, to develop effective strategies to suppress the formation of α-synuclein aggregates and their associated toxicity (8,9), because the mechanism of aggregation of this protein is extremely complex and highly dependent on environmental factors, such as pH, temperature, and contact with surfaces (10). In particular, it is well established that phospholipid binding can accelerate fibril formation (11); moreover, it has recently been shown that such acceleration occurs through the enhancement of the initial primary nucleation step in the aggregation process (12).…”

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…Computational unfoldomics is a recently proposed, emerging concept, which identifies metastable structures by simulations coupled with virtual screen of potential inhibitors [53]. In silico high-throughput structure-based docking screen combined with experiments was successfully applied to identify a druggable small molecule which ameliorates SYN-mediated dysfunction in cell models [56]. These studies are promising; however, none of them takes into account the effect of the inhibitors on the physiological functions of IDPs.…”

Intrinsically Disordered Proteins: Controlled Chaos or Random Walk

“…Furthermore, IDPs have been recent targets for therapeutic strategies for mammalian diseases such as Parkinson's disease. 55 Similarly, IDPs found in plants could be targets for decreasing crops' susceptibility to disease or increasing overall yield. Additional research could focus on identifying key IDP targets for both therapeutics and plant resistance.…”