Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 15, Issue 34, Pages 3968-3976Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161209789649321
Keywords
Parkinson's disease; drug discovery; quality control systems; aging; alpha-synuclein; synucleinopathies; aggregation; neurotoxic oligomers
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Funding
- Michael J. Fox Foundation
- Fundacao para a Ciencia e Tecnologia
- Alto Comissariado para a Saude
- EMBO Installation
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The heterogeneity of symptoms and disease progression observed in synucleinopathies, of which Parkinson's disease (PD) is the most common representative, poses large problems for its treatment and for the discovery of novel therapeutics. The molecular basis for pathology is currently unclear, both in familial and in sporadic cases. While the therapeutic effects of L-DOPA and dopamine receptor agonists are still the gold standards for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for these disorders faces significant challenges due to the poor knowledge of the putative targets involved. Recent experimental evidence strongly suggests a central role for neurotoxic alpha-synuclein oligomeric species in neurodegeneration. The events leading to protein oligomerization, as well as the oligomeric species themselves, are likely amenable to modulation by small molecules, which are beginning to emerge in high throughput compound screens in a variety of model organisms. The therapeutic potential of small molecule modulators of oligomer formation demands further exploration and validation in cellular and animal disease models in order to accelerate human drug development.
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