Title: Drug targeting of the Pathological Homo- and Hetero-Associations of Alpha-Synuclein in the Parkinsonism

Abstract

With the aging of the population, Parkinson’s disease (PD) poses a serious socio-economic problem; there is no effective treatment so far for the disease. The hallmarks of PD and other synucleinopathies are the disordered alpha-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25), the latter discovered by our lab. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically SYN is involved in neuronal plasticity modulation, while TPPP/p25 regulates the dynamics/stability of the microtubule network, crucial for oligodendrocyte (OLG) differentiation. In a healthy brain, SYN and TPPP/p25 occur predominantly in neurons and OLGs, respectively; however, in pathological cases they are co-enriched and co-localized in both cell types. The pathomechanisms of these diseases are largely unknown; the fatal species are the small, soluble homo- and hetero-associations of SYN, the aggregates/inclusions are formed at the later stage of the diseases. However, both SYN and TPPP/p25 with their high conformational plasticity and chameleon feature are challenging drug targets. Nevertheless, we have established a new strategy based upon specific protein-protein targeting: the contact surface of pathological SYN-TPPP/p25 associations has been validated, which can overcome the challenges. This innovative strategy could permit the development of unique and efficient drugs for the medical treatment of parkinsonism.