Review Article

Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein

Authors: Ming-ming Xu1, Philip Ryan2,3,4, Santosh Rudrawar2,3,4, Ronald J Quinn1, Hai-yan Zhang5, George D Mellick1
1 Griffith Institute for Drug Discovery, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan, QLD 4111, Australia
2 School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia
3 Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia
4 Quality Use of Medicines Network, Griffith University, Gold Coast, QLD 4222, Australia
5 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to: Ming-ming Xu: manny.xu@griffithuni.edu.au, George D Mellick: g.mellick@griffith.edu.au,
DOI: 10.1038/s41401-019-0304-y
Received: 26 May 2019
Accepted: 29 August 2019
Advance online: 4 October 2019

Abstract

Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies (LBs) and Lewy neurites, both of which contain the presynaptic protein alpha-synuclein (α-syn). Under normal conditions, native α-syn exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species, especially oligomers, can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, as well as other damage, leading to neuronal death and eventually neurodegeneration. Early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This review summarizes the progress toward discovering imaging probes and aggregation inhibitors for α-syn. Relevant strategies and techniques in the discovery of α-syn-targeted drugs are also discussed.
Keywords: Parkinson’s disease; alpha-synuclein; imaging probes; aggregation inhibitors; thioflavin-T; mass spectrometry

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