Scaffolding protein Homer1a protects against NMDA-induced neuronal injury

Wang, Y; Rao, Wei; Zhang, C; Zhang, C; Liu, M-d; Han, Feng; Yao, Ling; Han, Hua; Luo, Peng; Su, Ning; Fei, Z

doi:10.1038/cddis.2015.216

Cited by 38 publications

(29 citation statements)

References 69 publications

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“…Increased Homer1a expression attenuated neuronal injury induced by mGluR1 activation in a model of traumatic brain injury (Luo et al, 2014) and reduced Ca 2+ overload and neuronal injury in a MPP(+)-toxicity model with cultured rat mesencephalic cells (Zeng et al, 2013). Increased Homer1a expression was also recently demonstrated to exert neuroprotective effects against NMDA-induced neuronal injury (Wang et al, 2015b). Interestingly, expression of homer1a has been shown to be elevated following inhibition of neuronal SOC in PC12 cells, suggesting potential cross-talk between SOC and Homer1a expression in neuronal cells (Li et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

104

149

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The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2+ release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2+ levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca2+ release, ER Ca2+ levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD.

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Section: Discussionmentioning

confidence: 97%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

104

149

View full text Add to dashboard Cite

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“…Due to these structural features, Homer1a acts as a dominant-negative protein that disrupts the complexes formed by long Homers and regulates downstream signaling (Xiao et al, 2000 ). Our previous studies have demonstrated that Homer1a protects neurons against various stresses by regulating metabolic glutamate receptors, N-methyl-D-aspartate receptors, and store-operated calcium entry (Luo et al, 2014 ; Wang et al, 2015 ; Rao et al, 2016 ). We also found that Homer1a attenuates H 2 O 2 -induced oxidative stress by reducing ROS accumulation in PC12 cells (Luo et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Luo

Rao

et al. 2018

Front. Neurosci.

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Neuronal oxidative stress is involved in diverse neurological disorders. Homer1a, as an important member of the Homer family and localized at the postsynaptic density, is known to protect cells against oxidative injury. However, the exact neuroprotective mechanism of Homer1a has not been fully elucidated. Here, we found that Homer1a promoted cell viability and reduced H2O2-induced LDH release. The overexpression of Homer1a enhanced autophagy after H2O2 treatment, which was confirmed by increased expression of LC3II, Beclin-1, and greater autophagosome formation. In addition, we demonstrated that activating autophagy improved cell survival and reduced H2O2-induced oxidative stress and mitochondrial damage. Moreover, the autophagy inhibitor 3-MA partially prevented the protective effects of Homer1a against oxidative challenge. We also found that the upregulation of Homer1a after H2O2 treatment increased the phosphorylation of AMPK. Furthermore, the AMPK inhibitor compound C inhibited Homer1a-induced autophagy and abolished Homer1a-mediated neuroprotection. All the above data suggests that Homer1a confers protection against H2O2-induced oxidative damage via AMPK-dependent autophagy.

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“…One protein that may play an important role in glutamate-induced calcium dysregulation is Homer1a, an intensively-studied immediate early gene (IEG) that belongs to the postsynaptic protein family. Previous studies have demonstrated that Homer1a is extensively involved in neuronal calcium signals, affecting not only metabolic glutamate receptors (mGluR), but also iGluRs, particularly N-methyl-D-aspartate receptor 12 13 14 15 16 . These functions are mostly attributed to its structural features.…”

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confidence: 99%

“…Additionally, the inhibition of SOCE alleviated oxidative stress-induced cell injury in HT-22 cells by reducing calcium influx 8 26 . Because Homer1a lacks the CC domain, and therefore cannot self-multimerize, Homer1a might act as a negative competitor of Homer1b/c, disturbing the Homer1b/c-calcium channel complexes, and therefore play a role in the cell’s response to oxidative stress 12 13 27 . However, whether Homer1a plays a role in glutamate-induced HT-22 injury or can alter glutamate-induced calcium influx has not been elucidated.…”

mentioning

confidence: 99%

Homer1a attenuates glutamate-induced oxidative injury in HT-22 cells through regulation of store-operated calcium entry

Rao

Peng

Zhang

et al. 2016

Sci Rep

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Calcium disequilibrium is extensively involved in oxidative stress-induced neuronal injury. Although Homer1a is known to regulate several neuronal calcium pathways, its effects on, or its exact relationship with, oxidative stress-induced neuronal injury has not yet been fully elucidated. We found that Homer1a protected HT-22 cells from glutamate-induced oxidative stress injury by inhibiting final-phase intracellular calcium overload and mitochondrial oxidative stress. In these cells, stromal interactive molecule 1 (STIM1) puncta, but not the protein level, was significantly increased after glutamate treatment. Store-operated calcium entry (SOCE) inhibitors and cells in which a key component of SOCE (STIM1) was knocked out were used as glutamate-induced oxidative stress injury models. Both models demonstrated significant improvement of HT-22 cell survival after glutamate treatment. Additionally, increased Homer1a protein levels significantly inhibited SOCE and decreased the association of STIM1-Orai1 triggered by glutamate. These results suggest that up-regulation of Homer1a can protect HT-22 cells from glutamate-induced oxidative injury by disrupting the STIM1-Oria1 association, and then by inhibiting the SOCE-mediated final-phrase calcium overload. Thus, regulation of Homer1a, either alone or in conjunction with SOCE inhibition, may serve as key therapeutic interventional targets for neurological diseases in which oxidative stress is involved in the etiology or progression of the disease.

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Scaffolding protein Homer1a protects against NMDA-induced neuronal injury

Cited by 38 publications

References 69 publications

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Homer1a attenuates glutamate-induced oxidative injury in HT-22 cells through regulation of store-operated calcium entry

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