The good and bad of therapeutic strategies that directly target α‐synuclein

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 peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation 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 overexpression, 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 formation, 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.

Behavioral Deficits and Brain α-Synuclein and Phosphorylated Serine-129 α-Synuclein in Male and Female Mice Overexpressing Human α-Synuclein

“…α-syn has been reported to have both "good" and "bad" effects on neuronal activity and communication [51,52]. It is a presynaptic molecule and involved in the maintenance of synaptic vesicle binding and trafficking, and different forms of α-syn may play various roles in normal cellular functions and disease pathogenesis [49,53].…”

Hydrogen Sulfide and β-Synuclein Are Involved and Interlinked in the Aging Glaucomatous Retina

“…e underlying mechanism, through which H 2 S exerts its neuroprotection, was partly attributed to its capability of vasorelaxation, antioxidative stress, neuroendocrine regulation, and inflammation suppression [20][21][22]. Moreover, H 2 S is involved in several mutual pathophysiological processes with SNCB, such as microglia activation, p53-mediated apoptosis, inflammatory response, and free radical reactions [8,11,41,42].…”

“…Studies have shown that H 2 S and synucleins are involved in several mutual pathophysiological processes, such as microglia activation, p53-mediated apoptosis, inflammatory response, and free radical reactions [8,11,41,42]. Purpose of this study is to first elucidate the potential roles and functions of synucleins in glaucomatous neuropathy, following this, to investigate the potential of H 2 S to regulate it and to better understanding the mechanism of H 2 S in neuroprotection.…”

Hydrogen Sulfide: Novel Endogenous and Exogenous Modulator of Oxidative Stress in Retinal Degeneration Diseases

“…SNCB was found to form toxic cytoplasmic inclusion bodies in a manner similar to SNCA and has similar toxic mechanisms, including vesicle transport damage and OS induction [ 130 ]. H 2 S is involved in some pathophysiological processes that interact with SNCB, such as microglia activation, p53-mediated apoptosis, inflammatory response, and free radical reaction [ 121 , 131 , 132 , 133 ].…”