Challenging drug target for Parkinson's disease

Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Tibor Szénási, J. Oláh, Adél Szabó, Sándor Szunyogh, András Láng, A. Perczel, Attila Lehotzky, Vladimir N. Uversky, J. Ovádi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178–187 aa and 147–156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.

Original languageEnglish
Pages (from-to)310-323
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

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Synucleins
alpha-Synuclein
Lizards
Parkinson Disease
Tubulin
Pharmaceutical Preparations
Proteins
Protein Transport
Computational Biology
Polymerization
Brain

Keywords

  • Bimolecular fluorescence complementation
  • Deletion mutants
  • Drug target
  • Protein chameleon
  • Tubulin Polymerization Promoting Protein/p25
  • α-Synuclein

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Challenging drug target for Parkinson's disease : Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins. / Szénási, Tibor; Oláh, J.; Szabó, Adél; Szunyogh, Sándor; Láng, András; Perczel, A.; Lehotzky, Attila; Uversky, Vladimir N.; Ovádi, J.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1863, No. 1, 01.01.2017, p. 310-323.

Research output: Contribution to journalArticle

Szénási, Tibor ; Oláh, J. ; Szabó, Adél ; Szunyogh, Sándor ; Láng, András ; Perczel, A. ; Lehotzky, Attila ; Uversky, Vladimir N. ; Ovádi, J. / Challenging drug target for Parkinson's disease : Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2017 ; Vol. 1863, No. 1. pp. 310-323.
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