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Pharmacological targeting of α‐synuclein and TPPP /p25 in Parkinson's disease: challenges and opportunities in a Nutshell
Author(s) -
Oláh Judit,
Ovádi Judit
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13464
Subject(s) - parkinson's disease , pathogenesis , medicine , synucleinopathies , neuroscience , peptidomimetic , neurodegeneration , microbiology and biotechnology , population , disease , microtubule , alpha synuclein , bioinformatics , chemistry , biology , biochemistry , pathology , environmental health , peptide
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 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.