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

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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.

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Fig. 1
Scheme 1
Fig. 2
Fig. 3

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

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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.

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Authors and Affiliations

  1. Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Nuno Vale & Sara Silva

  2. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho, 45, 4200-135, Porto, Portugal

    Nuno Vale & Sara Silva

  3. Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal

    Nuno Vale & Sara Silva

  4. Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal

    Nuno Vale

  5. Department of Chemistry and Biochemistry, Faculty of Sciences, LAQV/REQUIMTE, University of Porto, Rua do Campo Alegre, 687, 4169-007, Porto, Portugal

    Cláudia Alves & Paula Gomes

  6. Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany

    Vaishali Sharma, Diana F. Lázaro & Tiago Fleming Outeiro

  7. Max Planck Institute for Experimental Medicine, Göttingen, Germany

    Tiago Fleming Outeiro

  8. Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Tiago Fleming Outeiro

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  1. Nuno Vale
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  2. Cláudia Alves
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  3. Vaishali Sharma
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  4. Diana F. Lázaro
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  6. Paula Gomes
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Correspondence to Nuno Vale.

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Vale, N., Alves, C., Sharma, V. et al. A new MAP-Rasagiline conjugate reduces α-synuclein inclusion formation in a cell model. Pharmacol. Rep 72, 456–464 (2020). https://doi.org/10.1007/s43440-019-00032-x

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