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A new MAP-Rasagiline conjugate reduces α-synuclein inclusion formation in a cell model

  • Nuno ValeEmail author
  • Cláudia Alves
  • Vaishali Sharma
  • Diana F. Lázaro
  • Sara Silva
  • Paula Gomes
  • Tiago Fleming Outeiro
Short Communication
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Abstract

Background

Parkinson’s disease (PD) is the second most common neurodegenerative disease of the elderly. Current therapies are only symptomatic, and have no disease-modifying effect. Therefore, disease progresses continuously over time, presenting with both motor and non-motor features. The precise molecular basis for PD is still elusive, but the aggregation of the protein alpha-synuclein (α-syn) is a key pathological hallmark of the disease and is, therefore, a major focus of current research. Considering the intrinsic properties of cell-penetrating peptides (CPPs) for mediating drug delivery of neurotherapeutics across the blood brain barrier (BBB), these might open novel opportunities for the development of new solutions for the treatment of brain-related aspects of PD and other neurodegenerative disorders.

Methods

Here, we synthesized solid-phase CPPs using an amphipathic model peptide (MAP) conjugated with the drug Rasagiline (RAS), which we named RAS-MAP, and evaluated its effect on α-syn inclusion formation in a human cell-based model of synucleinopathy.

Results

We found that treatment with RAS-MAP at low concentrations (1–3 µM) reduced α-syn aggregation in cells.

Conclusions

For the first time, we report that conjugation of a current drug used in the therapy of PD with CPP reduces α-syn aggregation, which might prove beneficial in PD and other synucleinopathies.

Graphic abstract

Keywords

Alpha-synuclein Cell-penetrating peptides Lewy bodies Parkinson’s disease Rasagiline 

Abbreviations

α-syn

Alpha-synuclein

BBB

Blood brain barrier

CNS

Central nervous system

CPP

Cell-penetrating peptide

DA

Dopamine

DMF

Dimethyformanide

HPLC

High-pressure liquid chromatography

MAO-B

Monoamide oxidase B

MAP

Amphipathic model peptide

NMS

Non-motor symptoms

PD

Parkinson’s disease

RAS

Rasagiline

RP-MPLC

Reverse-phase medium-pressure liquid chromatography

SD

Standard deviation

TEMPO

TVP-1012 in early monotherapy for PD outpatients

ADAGIO

Attenuation of disease progression with Azilect given once—daily

PRESTO

Parkinson’s Rasagiline: efficacy and safety in the treatment of “Off”

LARGO

Lasting effect in adjunct therapy with Rasagiline given once—daily

Notes

Acknowledgements

This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and through project IF/00092/2014/CP1255/CT0004. SS thanks her PhD Grant (PD/BD/135456/2017) from FCT. NV thanks FCT by IF position, Fundação Manuel António da Mota (FMAM, Portugal) and Pfizer Portugal by support Nuno Vale Lab. NV and PG thank Dr. Marco Colombo, from Dipharma, for the supply of Rasagiline used in the first phase of the work. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT, FMAM or Pfizer Portugal. TFO was supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).

Funding

This work has been financed by the Portuguese founds from Fundação para a Ciência e a Tecnologia (FCT), through of Grant Number IF/00092/2014/CP1255/CT0004.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

43440_2019_32_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1187 kb)

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Copyright information

© Maj Institute of Pharmacology Polish Academy of Sciences 2020

Authors and Affiliations

  • Nuno Vale
    • 1
    • 2
    • 3
    • 4
    Email author
  • Cláudia Alves
    • 5
  • Vaishali Sharma
    • 6
  • Diana F. Lázaro
    • 6
  • Sara Silva
    • 1
    • 2
    • 3
  • Paula Gomes
    • 5
  • Tiago Fleming Outeiro
    • 6
    • 7
    • 8
  1. 1.Laboratory of Pharmacology, Department of Drug Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  2. 2.Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)PortoPortugal
  3. 3.Instituto de Investigação e Inovação em Saúde (i3S)University of PortoPortoPortugal
  4. 4.Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS)University of PortoPortoPortugal
  5. 5.Department of Chemistry and Biochemistry, Faculty of Sciences, LAQV/REQUIMTEUniversity of PortoPortoPortugal
  6. 6.Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the BrainUniversity Medical Center GöttingenGöttingenGermany
  7. 7.Max Planck Institute for Experimental MedicineGöttingenGermany
  8. 8.Institute of Neuroscience, The Medical SchoolNewcastle UniversityNewcastle upon TyneUK

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