A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

Abstract

With the aging of the population, Parkinson’s disease poses a serious socio-economic problem; there is no effective therapy that can arrest/revert the progression of the disease. The hallmarks of Parkinson’s disease and other synucleinopathies are the disordered alpha-synuclein and TPPP/p25. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically TPPP/p25 regulates the dynamics/stability of the microtubules and is crucial for oligodendrocyte differentiation; while alpha-synuclein is involved in neuronal plasticity modulation and synaptic vesicle pool maintenance. In healthy brain, alpha-synuclein and TPPP/p25 occur predominantly in neurons and oligodendrocytes, respectively; however, they are co-enriched and co-localized in both cell types in brain inclusions in the cases of Parkinson’s disease and multiple system atrophy, respectively. The pathomechanisms of these diseases are largely unknown; the fatal species are the small, soluble homo- and hetero-associations of alpha-synuclein. These proteins with their high conformational plasticity and chameleon feature are challenging drug targets. Nevertheless, the contact surface of TPPP/p25-alpha-synuclein assemblies has been validated as a specific drug target. This new strategy with innovative impact, namely targeting the interface of the TPPP/p25-alpha-synuclein complex, could contribute to the development of anti-Parkinson drugs with unique specificity.