Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease

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Runeberg-Roos , P , Piccinini , E , Penttinen , A-M , Matlik , K , Heikkinen , H , Kuure , S , Bespalov , M M , Peranen , J , Garea-Rodriguez , E , Fuchs , E , Airavaara , M , Kalkkinen , N , Penn , R & Saarma , M 2016 , ' Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease ' , Neurobiology of Disease , vol. 96 , pp. 335-345 . https://doi.org/10.1016/j.nbd.2016.07.008

Title: Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease
Author: Runeberg-Roos, Pia; Piccinini, Elisa; Penttinen, Anna-Maija; Matlik, Kert; Heikkinen, Hanna; Kuure, Satu; Bespalov, Maxim M.; Peranen, Johan; Garea-Rodriguez, Enrique; Fuchs, Eberhard; Airavaara, Mikko; Kalkkinen, Nisse; Penn, Richard; Saarma, Mart
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Laboratory Animal Centre
University of Helsinki, Research Programs Unit
University of Helsinki, Medicum
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2016-12
Language: eng
Number of pages: 11
Belongs to series: Neurobiology of Disease
ISSN: 0969-9961
URI: http://hdl.handle.net/10138/229290
Abstract: In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue. (C) 2016 Elsevier Inc. All rights reserved.
Subject: NRTN
Neurturin
GDNF
GFR alpha l
GFR alpha 2
RET
Heparan sulfate
Heparin
Parkinson's disease
Growth factor
MIDBRAIN DOPAMINERGIC-NEURONS
NEUROTROPHIC FACTOR
HEPARIN-BINDING
RECEPTOR-BINDING
CONTROLLED-TRIAL
MESSENGER-RNA
GENE-TRANSFER
INFUSION
GFR-ALPHA-1
3112 Neurosciences
3124 Neurology and psychiatry
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