The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson’s disease patients.
Sci Rep. 2019-06-20; 9(1):
DOI: 10.1038/s41598-019-45419-1
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1. Sci Rep. 2019 Jun 20;9(1):8898. doi: 10.1038/s41598-019-45419-1.
The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia
nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson’s
disease patients.
Nuzzo T(1), Punzo D(2)(3), Devoto P(4), Rosini E(5), Paciotti S(6), Sacchi S(5),
Li Q(7)(8), Thiolat ML(9)(10), Véga C(9), Carella M(1), Carta M(4), Gardoni
F(11), Calabresi P(12), Pollegioni L(5), Bezard E(7)(8)(9)(10), Parnetti L(12),
Errico F(13), Usiello A(14)(15).
Author information:
(1)Translational Neuroscience Unit, IRCCS Casa Sollievo della Sofferenza, 71013,
San Giovanni Rotondo, Italy.
(2)Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145,
Naples, Italy.
(3)Department of Environmental, Biological and Pharmaceutical Science and
Technologies, Università degli Studi della Campania « Luigi Vanvitelli », 81100,
Caserta, Italy.
(4)Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato,
Italy.
(5)Department of Biotechnology and Life Sciences, Università degli Studi
dell’Insubria, 21100, Varese, Italy.
(6)Department of Pharmaceutical Sciences, University of Perugia, 06122, Perugia,
Italy.
(7)Motac Neuroscience, UK-M15 6WE, Manchester, United Kingdom.
(8)Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing,
China.
(9)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France.
(10)Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293,
Institut des Maladies Neurodégénératives, Bordeaux, France.
(11)Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università
degli Studi di Milano « La Statale », 20133, Milan, Italy.
(12)Department of Medicine, Neurology Clinic, University Hospital of Perugia,
06129, Perugia, Italy.
(13)Department of Agricultural Sciences, University of Naples « Federico II »,
80055, Portici, Italy. .
(14)Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145,
Naples, Italy. .
(15)Department of Environmental, Biological and Pharmaceutical Science and
Technologies, Università degli Studi della Campania « Luigi Vanvitelli », 81100,
Caserta, Italy. .
Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to
contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and
to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other
amino acids in the atypical D-configuration, D-serine and D-aspartate, activate
NMDARs. In the present work, we investigated the effect of dopamine depletion on
D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the
serum and cerebrospinal fluid of PD patients. We found that MPTP treatment
increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues
both D-amino acids levels. Conversely, dopaminergic denervation is associated
with selective D-serine reduction in the substantia nigra. Such decrease suggests
that the beneficial effect of D-serine adjuvant therapy previously reported in PD
patients may derive from the normalization of endogenous D-serine levels and
consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine
binding site. We also found reduced D-serine concentration in the cerebrospinal
fluid of L-DOPA-free PD patients. These results further confirm the existence of
deep interaction between dopaminergic and glutamatergic neurotransmission in PD
and disclose a possible direct influence of D-amino acids variations in the
changes of NMDAR transmission occurring under dopamine denervation and L-DOPA
therapy.
DOI: 10.1038/s41598-019-45419-1
PMCID: PMC6586824
PMID: 31222058