Trends in Molecular Medicine
ReviewChemical Chaperones as Novel Drugs for Parkinson’s Disease
Section snippets
α-Syn: A Therapeutic Target in PD
Synucleinopathies are a series of heterogeneous neurodegenerative disorders that affect >10 million people worldwide. No neuroprotective or neurorestorative therapies are currently available for synucleinopathies, which include PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation [1., 2., 3., 4.]. These diseases all share common neuropathological features and are characterized by the accumulation of deposits of the protein α-syn
α-Syn Misfolding and Aggregation
α-Syn is abundant in neuronal cells and is involved in synaptic transmission where it contributes to the release of synaptic vesicles and synaptic membrane recycling [15]. In healthy neurons, α-syn is found either bound to membranes or in a monomeric, soluble and disordered form in the cytosol, and the two species interconvert in a rapid equilibrium. It has been suggested that α-syn can also form helical tetramers in the cytoplasm [16], but this possibility remains under debate [17]. During
Targeting α-Syn Aggregation
Different α-syn-targeted strategies and tools have been developed in recent years to modulate its misfolding and aggregation in the context of synucleinopathies. These strategies include: (i) SNCA gene-silencing approaches to knock out or decrease the neuronal levels of the protein, (ii) strategies to increase the clearance of soluble or aggregated α-syn by potentiating autophagic and proteasomal activities, and (iii) agents aimed at preventing the formation and/or propagation of the toxic
Natural Compounds: Establishing the Foundation for α-Syn-Targeted Therapies for PD
Natural compounds represent a major source of medications and important structural scaffolds to develop new drugs, and many of them interact specifically with biological macromolecules, mainly proteins. The ability of small molecules to interfere with α-syn aggregation was first reported in the early 2000s. Analysis of 169 molecules revealed that several natural catecholamines, including dopamine, L-dopa, epinephrine, and norepinephrine, were able to inhibit the formation of α-syn amyloid
Drug Repositioning: A Shortcut for α-Syn-Targeted Therapies
Drug discovery is characterized by high attrition rates that are mainly attributed to a lack of pharmacological efficacy, deficient safety profiles, or both. In addition to its intrinsic high risk, the economic investment required for such research initiatives is huge, averaging 5–10 million USD per molecule. In this context, drug repositioning offers an opportunity to reduce the risks and costs of therapeutic development. Successful therapies in cancer and in cardiovascular and
Rational Drug Design: De Novo Discovery of α-Syn Aggregation Inhibitors
The intrinsically disordered nature of α-syn and the complexity of the aggregation process preclude the use of conventional drug discovery strategies which typically exploit 3D protein structures to design drugs that dock into protein binding pockets or protein–protein interaction sites [85., 86., 87.]. In the case of α-syn, rational discovery usually targets protein residues involved in the weak noncovalent intermolecular contacts that initiate α-syn dimerization and/or oligomerization. CLR01
Expanding the Molecular Repertoire: High-Throughput Screening of Large Drug-like Collections
A powerful alternative for the discovery of novel active molecules is high-throughput screening of large collections of chemically diverse compounds. These initiatives necessarily rely on optimized assays that attempt to minimize time and cost per test while preserving specificity and sensitivity. The stochastic nature of protein aggregation impacts on experimental reproducibility and thus compromises hit selection by this type of 'brute force' approach. Notably, by optimizing α-syn aggregation
Concluding Remarks
Despite decades of investigation, PD remains incurable, and only symptomatic therapies are available. We have compiled a battery of promising small molecules that target the presumed origin of the disease, the aggregation of α-syn (Figure 3 and Table 1). Their mechanism of action is strongly influenced by the way in which they have been discovered: rationally designed molecules usually target the monomeric or early oligomeric states, whereas compounds identified by high-throughput screening
Acknowledgments
This work was funded by the Spanish Ministry of Economy and Competitiveness (grant BIO2016-78310-R to S.V.) and by the Institución Catalana de Investigación y Estudios Avanzados (ICREA; grant ICREA-Academia 2015 to S.V.).
Glossary
- Bradykinesia
- one of the most common symptoms of PD. It is characterized by an unusual slowness and a lack of accuracy in carrying out voluntary body movements.
- Cmax
- maximum concentration, a pharmacokinetic parameter to evaluate the bioavailability of a particular drug in a given tissue. It allows the drug dose to be adjusted according to the therapeutic concentration window.
- Cross-β-sheet fold
- the intermolecular stacking of parallel or antiparallel β-strands along the fibrillar axis is an amyloid
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Calcium promotes α-synuclein liquid-liquid phase separation to accelerate amyloid aggregation
2022, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The mechanisms and modulations of α-Syn aggregation have attracted much attention. Many efforts have been performed on the strategy of targeting α-Syn aggregations to cure PD [16,17,55]. Recent studies reported that α-Syn undergoes LLPS, accelerating the primary nucleation of amyloid aggregation [39].
Manganese promotes α-synuclein amyloid aggregation through the induction of protein phase transition
2022, Journal of Biological ChemistryCitation Excerpt :However, these solid-like condensates keep the ability to recruit soluble α-Syn monomers to enlarge the aggregates. The aggregation of α-Syn serves as a promising target for PD therapies, and this strategy has been extensively studied for many years (16, 22, 76). Successful drug candidates may target any of the stages during α-Syn aggregation.
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