Abstract
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 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 constitute good options for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for PD and other synucleinopathies faces significant challenges due to the poor knowledge of the putative targets. Recent experimental evidence strongly suggests a central role for neurotoxic α-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.
Highlights
Protein conformational disorders are a group of diseases associated with the misfolding and aggregation of one or more proteins
While extensive studies support a major role of molecular chaperones in synucleinopathies as well as in other neurodegenerative diseases, neither these quality control (QC) components nor those which gene products are defective in familial Parkinson’s disease (PD) are easy drug targets for small molecules
The primary pathological role proposed for aSyn oligomeric species in neurodegeneration is consistent with the growing number of experimental evidence
Summary
Protein conformational disorders are a group of diseases associated with the misfolding and aggregation of one or more proteins. Be important to continue to develop cell models which recapitulate the molecular mechanisms of disease and where the conformation of these proteins can be readily assessed and manipulated. While extensive studies support a major role of molecular chaperones in synucleinopathies as well as in other neurodegenerative diseases, neither these QC components nor those which gene products are defective in familial PD are easy drug targets for small molecules.
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