CRITICAL REVIEW The good and bad of therapeutic strategies that directly target α-synuclein Francesca Longhena | Gaia Faustini | Viviana Brembati | Marina Pizzi | Arianna Bellucci Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy Correspondence Arianna Bellucci, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia (BS), Italy. Email: arianna.bellucci@unibs.it Funding information Fondazione Cariplo, Grant/Award Number: 2014-0769; Michael J. Fox Foundation for Parkinson's Research, Grant/Award Numbers: 10742, 10742.01; Ministero dell'Istruzione, dell'Università e della Ricerca, Grant/Award Number: PNR 2015-2020; Università degli Studi di Brescia, Grant/Award Number: BIOMANE Abstract Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α-synuclein (α-syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α-syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α-syn pathology. This poses the question of which is the most toxic α-syn species. What is worst, α-syn appears as a very pecu- liar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conforma- tion is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α-helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α-syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or over- expression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α-syn levels, oligomer forma- tion, fibrillation, or cell-to-cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α-syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state-of-the-art α-syn biology. Abbreviations: AD, Alzheimer's disease; Aβ, amyloid β; DAT, dopamine transporter; DLB, dementia with Lewy bodies; EGCG, (-)-epigallocatechin gallate; GABA, gamma-aminobutyric acid; GAIM, general amyloid interaction motif; GCI, glial cytoplasmic inclusions; LB, Lewy bodies; LN, Lewy neurites; MSA, multiple system atrophy; NAC, non-amyloid component; PcTS, cyclic tetrapyrrole phthalocyanine tetrasulfonate; PD, Parkinson's disease; SNARE, soluble NSF attachment protein receptors; SNCA, alpha-synuclein gene locus; SV2C, synaptic vesicle glycoprotein 2C; VMAT2, vesicular monoamine transporter 2; α-syn, alpha-synuclein. Received: 29 August 2019 Accepted: 12 October 2019 DOI: 10.1002/iub.2194 © 2019 International Union of Biochemistry and Molecular Biology IUBMB Life. 2019;1–11. wileyonlinelibrary.com/journal/iub 1