Pharmacological targeting of α-synuclein and TPPP/p25 in Parkinson's disease

Oláh, Judit and Ovádi, Judit (2019) Pharmacological targeting of α-synuclein and TPPP/p25 in Parkinson's disease. FEBS LETTERS, 593 (13). pp. 1641-1653. ISSN 0014-5793

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Abstract

With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio-economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co-enriched and co-localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we propose a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN-TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention. This article is protected by copyright. All rights reserved.

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