Journal
FEBS LETTERS
Volume 593, Issue 13, Pages 1641-1653Publisher
WILEY
DOI: 10.1002/1873-3468.13464
Keywords
drug target; innovative strategy; moonlighting protein; Parkinsonism; TPPP; p25; unstructured protein; alpha-synuclein
Funding
- European Concerted Research Action COST Action [TD1406]
- Hungarian National Scientific Research Fund Grant OTKA [T-112144]
- Richter Gedeon Nyrt granted project [6567-19 403 VT]
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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, alpha-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 established 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.
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