Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

doi:10.1007/s11515-016-1425-z

Front. Biol.

2016, Vol. 11

Issue (6) : 439-458 https://doi.org/10.1007/s11515-016-1425-z

REVIEW

Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

Kimberly D. Girling,Yu Tian Wang(

)

Djavad Mowafahian Centre for Brain Health & Department of Medicine, University of British Columbia, V6T 1Z3, Canada

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Abstract

BACKGROUND: Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors (NMDARs) has been shown to have a key role in the neuropathogenesis of HD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell-survival activity of GluN2A-NMDARs.

OBJECTIVE: This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target.

METHODS: A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including “Huntington’s Disease,” “excitotoxicity,” “NMDAR” and “therapeutics.”

RESULTS: A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs.

CONCLUSION: The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.

Keywords Huntington’s Disease NMDA receptor excitotoxicity cell death therapeutics

Corresponding Author(s): Yu Tian Wang

Online First Date: 17 November 2016 Issue Date: 26 December 2016

Cite this article:

Kimberly D. Girling,Yu Tian Wang. Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease[J]. Front. Biol., 2016, 11(6): 439-458.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-016-1425-z
https://academic.hep.com.cn/fib/EN/Y2016/V11/I6/439

Fig.1 Dichotomous role of NMDARs in cell survival and cell death. Activation of synaptically located, primarily GluN2A-containing NMDARs is associated with a wide range of cell survival and plasticity-promoting signaling pathways. Activation of these receptors leads to increased CREB phosphorylation in the nucleus, driving transcription of a range of cell survival-promoting genes. GluN2A, synaptic NMDAR activation also activates calcium-dependent calcineurin, shown to be involved in LTP and plasticity. Similarly, synaptic, GluN2A-NMDARs promote signaling of several cell survival molecular pathways including ERK1/2, PI3K and BDNF. Conversely, extrasynaptic, primarily GluN2B-NMDARs are related to cell death signaling. These receptors inhibit many of the synaptic, GluN2A pathways, including CREB shutoff, inhibition of ERK1/2, BDNF and P13K, and signals many molecular pathways involved in cell death, including JNK, and p38 MAPK. Extrasynaptic GluN2B NMDARs also activate cleavage molecules caspase and m-calpain, involved in protein cleavage, apoptosis and cell death.

Fig.2 Schematic diagram of mHTT-dependent dysregulation in NMDAR expression and signaling in HD. Increased release from cortical (or thalamic) afferents stimulates NMDARs on medium spiny neurons in the striatum. Increased release and reduced reuptake from astrocytes leads to increased glutamate at the synapse, causing spillover and stimulating extrasynaptic, GluN2B-containing NMDARs, shown to be associated with cell death signaling. Increased NMDAR stimulation leads to increases in intracellular calcium, which stimulates increase in apoptotic signaling pathways, as well as activation of calcium-dependent molecules, such as caspases and calpains, which cleave mHTT into toxic fragments and stimulate cell death signaling. Calpain activation also leads to increased cleavage of GluN2B NMDARs, facilitating their movement from synaptic to extrasynaptic sites. Ca²⁺ also activates the calcium dependent molecule calcineurin, which subsequently activates STEP, which dephosphorylates and destabilizes synaptic NMDARs, reducing their expression. STEP also leads to the clathrin vesicle endocytosis of NMDARs, and their recycling to extasynaptic sites (not shown). mHTT influences PSD-95 interaction with NMDARs, interacting less strongly with GluN2A-NMDARs in the synapse, while stabilizing GluN2B-NMDARs extrasynaptically. Increased expression and stabilization of extrasynaptic NMDARs leads to increased sensitivity to NMDA, increased cell death and apoptotic signaling and dephosphorylation of CREB in the nucleus, leading to transcriptional dysregulation.

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