Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure

Navarria, Laura; Zaltieri, Michela; Longhena, Francesca; Spillantini, Maria Grazia; Missale, Cristina; Spano, PierFranco; Bellucci, Arianna

doi:10.1016/j.neuint.2015.03.008

Cited by 29 publications

(26 citation statements)

References 54 publications

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“…However, the mechanism through which α-syn abnormalities affect synaptic transmission remains unclear. Our ndings are consistent with recent ndings that pathological α-syn (i.e., A53T-and α-syn PFF) downregulates NMDAR synaptic content and functions [10,11,25,34,47]. Our study provides direct molecular evidence that pathological α-syn rapidly alters NMDAR tra cking, which affects the NMDAR synaptic content.…”

Section: Discussionsupporting

confidence: 92%

“…Aberrant NMDAR surface tra cking [18,25,64], distribution, and activity [65] are involved in the emergence of neurological [66,67] and psychiatric disorders [41,57]. In our study, we found that pathological α-syn alters NMDAR membrane dynamics.…”

Section: Discussionsupporting

confidence: 49%

“…NMDAR expression, activation, and endocytosis are signi cantly affected in different brain regions in PD animal models and patients [23][24][25][26][27][28][29][30]. Selective NMDAR blockers or antagonists have been shown to improve locomotor activity and ameliorate parkinsonism in several PD models [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

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Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

Huang¹,

Gou²,

Li³

et al. 2020

Preprint

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Background α-Synuclein misfolding and aggregation contribute to synaptic dysfunction in synucleinopathies, including Parkinson’s disease. However, the mechanism underlying the effect of α-synuclein on synaptic components remains unclear. Since the N-methyl-D-aspartic acid receptor (NMDAR) plays a key role in glutamate synapse pathophysiology, we here investigated its surface dynamics and functional distribution in neurons exposed to various pathological α-synuclein forms. Methods A combination of single-molecule tracking, immunochemistry, immunoblot and calcium imaging approaches were used to assess the changes in NMDAR membrane dynamics and functions. The NMDAR alterations were evaluated in rat cultured hippocampal networks, in which α-synuclein mutants were overexpressed or exposed to α-synuclein proteins (monomeric/PFF α-synuclein). The surface dynamics of NMDAR subtype was artificially tuned in order to test its instrumental role. Results We observed that mutant α-synuclein (A53T-α-synuclein) restricted NMDAR surface trafficking and impaired synaptic function. In contrast, wild-type α-synuclein did not affect synaptic NMDAR. Further, we found that chronic exposure to α-synuclein preformed fibrils induced molecular dysfunctions that mainly targeted the GluN2B-NMDAR subtype. The deficits of synaptic NMDAR have also been found in A53T transgenic mice α-synuclein. Upon fine-tuning of the surface dynamics of GluN2B-NMDAR, pathological α-synuclein gradually lost its synaptic toxicity. Conclusions Our findings indicate that pathological α-synuclein alters GluN2B-NMDAR synaptic dynamics and organization, which leads to glutamate synapse dysfunction.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 49%

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Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

Huang¹,

Gou²,

Li³

et al. 2020

Preprint

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“…α-synuclein was also shown to regulate complexin-1 and midbrain-specific factor forkhead box P1 expression 83 , enhance histone H3 lysine-9 (H3K9) dimethylation and promote H3K9me2-dependent transcriptional responses 84 , protect the functions of Hsp90 clients, such as Akt and mTOR, when the activity of Hsp90 is blocked 85 , stimulate protein phosphatase-2A (PP2A) activity and regulate tyrosine hydroxylase phosphorylation via the control of PP2A methylation 86 , modulate the trafficking and function of glutamate N-methyl-d-aspartate receptor 87 , and promote Notch1 intracellular domain degradation via interaction with the ubiquitin E3 ligase Fbw7 88 .…”

Section: Multifunctionality Anglementioning

confidence: 99%

Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

Uversky

2017

F1000Res

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Despite attracting the close attention of multiple researchers for the past 25 years, α-synuclein continues to be an enigma, hiding sacred truth related to its structure, function, and dysfunction, concealing mechanisms of its pathological spread within the affected brain during disease progression, and, above all, covering up the molecular mechanisms of its multipathogenicity, i.e. the ability to be associated with the pathogenesis of various diseases. The goal of this article is to present the most recent advances in understanding of this protein and its aggregation and to show that the remarkable structural, functional, and dysfunctional multifaceted nature of α-synuclein can be understood using the proteoform concept.

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“…Furthermore control and α-syn knock out groups demonstrated low percentages of neurons with Ca(II) abnormalities whereas the α-syn transgenic group showed Ca(II) response alteration, suggesting these alterations are related to α-syn expression (Reznichenko et al, 2012; Mironov, 2015). Furthermore, Navarria et al (2015) showed that overexpression of α-syn reduced NMDAR-mediated Ca(II) influx.…”

Section: α-Synuclein Aggregation Raised Ca(ii) and Oxidative Stressmentioning

confidence: 99%

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

et al. 2016

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Aggregation of the pre-synaptic protein, α-synuclein (α-syn), is the key etiological factor in Parkinson's disease (PD) and other alpha-synucleinopathies, such as multiple system atrophy (MSA) and Dementia with Lewy bodies (DLB). Various triggers for pathological α-syn aggregation have been elucidated, including post-translational modifications, oxidative stress, and binding of metal ions, such as calcium. Raised neuronal calcium levels in PD may occur due to mitochondrial dysfunction and/or may relate to calcium channel dysregulation or the reduced expression of the neuronal calcium buffering protein, calbindin-D28k. Recent results on human tissue and a mouse oxidative stress model show that neuronal calbindin-D28k expression excludes α-syn inclusion bodies. Previously, cell culture model studies have shown that transient increases of intracellular free Ca(II), such as by opening of the voltage-gated plasma calcium channels, could induce cytoplasmic aggregates of α-syn. Raised intracellular free calcium and oxidative stress also act cooperatively to promote α-syn aggregation. The association between raised neuronal calcium, α-syn aggregation, oxidative stress, and neurotoxicity is reviewed in the context of neurodegenerative α-syn disease and potential mechanism-based therapies.

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Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure

Cited by 29 publications

References 54 publications

Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

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