Pharmacological targeting of α-synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

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2 Citations (Scopus)

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 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.

Original languageEnglish
JournalFEBS letters
DOIs
Publication statusPublished - Jan 1 2019

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Synucleins
Parkinson Disease
Pharmacology
Intrinsically Disordered Proteins
Pharmaceutical Preparations
Peptidomimetics
Multiple System Atrophy
Protein Conformation
Proteins
Oligodendroglia
Tubulin
Nervous System Diseases
Polymerization
Neurons
Plasticity
Conformations
Brain
Aging of materials
Economics
Defects

Keywords

  • drug target
  • innovative strategy
  • moonlighting protein
  • Parkinsonism
  • TPPP/p25
  • unstructured protein
  • α-synuclein

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

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title = "Pharmacological targeting of α-synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell",
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 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.",
keywords = "drug target, innovative strategy, moonlighting protein, Parkinsonism, TPPP/p25, unstructured protein, α-synuclein",
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AU - Ovádi, J.

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