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Memantine exerts neuroprotective effects by modulating alpha-synuclein transmission in a parkinsonian model

Authors
 Ji Eun Lee  ;  Ha Na Kim  ;  Dong-Yeol Kim  ;  Yu Jin Shin  ;  Jin Young Shin  ;  Phil Hyu Lee 
Citation
 EXPERIMENTAL NEUROLOGY, Vol.344 : 113810, 2021-10 
Journal Title
EXPERIMENTAL NEUROLOGY
ISSN
 0014-4886 
Issue Date
2021-10
MeSH
Animals ; Cell Line ; Humans ; Memantine / pharmacology* ; Mice, Inbred C57BL ; Neurons / drug effects* ; Neurons / metabolism ; Neurons / pathology ; Neuroprotective Agents / pharmacology* ; Parkinsonian Disorders / metabolism ; Parkinsonian Disorders / pathology* ; Receptors, N-Methyl-D-Aspartate / drug effects ; Receptors, N-Methyl-D-Aspartate / metabolism ; alpha-Synuclein / drug effects* ; alpha-Synuclein / metabolism
Keywords
Memanitne ; NR2A subunits ; Parkinson's disease ; Receptor-mediated encodocytosis ; Transmission ; α-Synuclein
Abstract
Ample evidence has demonstrated that α-Synuclein can propagate from one area of the brain to others via cell-to-cell transmission, which might be the underlying mechanism for pathological propagation and the disease progression of Parkinson's disease (PD). Recent reports have demonstrated cell surface receptor-mediated cell-to-cell transmission of α-synuclein. Memantine decreased the levels of internalized cytosolic α-synuclein and led to attenuation in α-synuclein-induced cell death. Specifically, memantine attenuated α-synuclein-induced expression of clathrin and EEA1, and increased expression of NR2A subunits. Moreover, memantine inhibited propagation of extracellular α-synuclein and thus, decreased the expression of the phosphorylated form of α-synuclein in dopaminergic neurons of the substantia nigra, which was accompanied by increased survival of dopaminergic neurons with functional improvement of motor deficits. The present study demonstrated that memantine modulates extracellular α-synuclein propagation by inhibiting interactions between α-synuclein and NR2A subunits, which leads to neuroprotective effects on nigral dopaminergic neurons against α-synuclein-enriched conditions. The repositioning use of memantine in α-synuclein propagation needs to be further evaluated in patients with α-synucleinopathies as an effective therapeutic approach.
Full Text
https://www.sciencedirect.com/science/article/pii/S0014488621002181?via%3Dihub
DOI
10.1016/j.expneurol.2021.113810
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Jin Young(신진영)
Lee, Ji Eun(이지은)
Lee, Phil Hyu(이필휴) ORCID logo https://orcid.org/0000-0001-9931-8462
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187676
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